|
1
|
Shah AB, Cho H, Shim SH. Exploring the bioactive landscape: peptides and non-peptides from the human microbiota. NPJ Biofilms Microbiomes 2025; 11:76. [PMID: 40341751 PMCID: PMC12062242 DOI: 10.1038/s41522-025-00713-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/28/2025] [Indexed: 05/11/2025] Open
Abstract
The human microbiota, consisting of trillions of bacteria from six main phyla, produces peptide and non-peptide secondary metabolites which have antibacterial properties vital to medicine and biotechnology. These metabolites influence biological processes linked to diseases, yet much remains unknown. This review explores their structures and functions, aiming to spur novel metabolite discovery and advance drug development.
Collapse
Affiliation(s)
- Abdul Bari Shah
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Hyeonjae Cho
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Sang Hee Shim
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
| |
Collapse
|
|
2
|
Di Pierro F, Sagheddu V, Galletti S, Casaroli A, Labrini E, Soldi S, Cazzaniga M, Bertuccioli A, Matera M, Cavecchia I, Palazzi CM, Tanda ML, Zerbinati N. Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10522-5. [PMID: 40238037 DOI: 10.1007/s12602-025-10522-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2025] [Indexed: 04/18/2025]
Abstract
Among the emerging issues in probiotic safety, the possible presence of pks, a gene cluster synthetizing a genotoxin known as colibactin, is one of the most alarming. Indeed, indigenous E. coli strain pks-positive are found in 60% of patients with colorectal cancer, and the most widely used E. coli-based probiotic, known as E. coli Nissle 1917 (DSM 6601), is pks-positive. Starting from 25 potential candidates selected by screening 25 infant stool samples, we have selected an E. coli strain (named 5C, deposited as LMG S-33222) belonging to the phylotype A and having the serovar O173:H1. Having been previously completely sequenced by our group, we have further characterized this strain, demonstrating that it is (i) devoid of the most known potential pathogenic-related genes, (ii) devoid of possible plasmids, (iii) antibiotic-sensitive according to the EFSA panel, (iv) resistant in gastric and enteric juice, (v) significantly producing acetate, (vi) poorly producing histamine, (vii) endowed with a significant in vitro antipathogenic profile, (viii) promoting a significant in vitro immunological response based on IL-10 and IL-12, and (ix) devoid of the pks genes. A comparative genomics versus E. coli Nissle 1917 is also provided. Considering that the other two most commonly used E. coli-based probiotics (E. coli DSM 17252 and E. coli A0 34/86) are respectively pks-positive and alpha-hemolysin-(hly) and cytotoxic necrotizing factor-1-(cnf1) positive, this novel strain (E. coli 5C) is likely the probiotic E. coli strain with the best safety profile available to date for human use.
Collapse
Affiliation(s)
- Francesco Di Pierro
- Microbiota International Clinical Society, 10123, Turin, Italy
- Scientific & Research Department, Velleja Research, 20125, Milan, Italy
- Department of Medicine and Technological Innovation, University of Insubria, 21100, Varese, Italy
| | - Valeria Sagheddu
- AAT-Advanced Analytical Technologies, Fiorenzuola d'Arda, 29017, Piacenza, Italy
| | - Serena Galletti
- AAT-Advanced Analytical Technologies, Fiorenzuola d'Arda, 29017, Piacenza, Italy
| | - Alice Casaroli
- AAT-Advanced Analytical Technologies, Fiorenzuola d'Arda, 29017, Piacenza, Italy
| | - Edoardo Labrini
- AAT-Advanced Analytical Technologies, Fiorenzuola d'Arda, 29017, Piacenza, Italy
| | - Sara Soldi
- AAT-Advanced Analytical Technologies, Fiorenzuola d'Arda, 29017, Piacenza, Italy
| | | | - Alexander Bertuccioli
- Microbiota International Clinical Society, 10123, Turin, Italy
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61122, Urbino, Italy
| | - Mariarosaria Matera
- Microbiota International Clinical Society, 10123, Turin, Italy
- Department of Pediatric Emergencies, Misericordia Hospital, 58100, Grosseto, Italy
| | - Ilaria Cavecchia
- Microbiota International Clinical Society, 10123, Turin, Italy
- Microbiomic Department, Koelliker Hospital, 10134, Turin, Italy
| | | | - Maria Laura Tanda
- Endocrine Unit, Department of Medicine and Surgery, University of Insubria, 21100, Varese, Italy
| | - Nicola Zerbinati
- Department of Medicine and Technological Innovation, University of Insubria, 21100, Varese, Italy
| |
Collapse
|
|
3
|
Ye Z, Tan Q, Woltemate S, Tan X, Römermann D, Grassl GA, Vital M, Seidler U, Kini A. Escherichia coli Nissle Improves Short-Chain Fatty Acid Absorption and Barrier Function in a Mouse Model for Chronic Inflammatory Diarrhea. Inflamm Bowel Dis 2025; 31:1109-1120. [PMID: 39708301 PMCID: PMC11985405 DOI: 10.1093/ibd/izae294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Defects in SLC26A3, the major colonic Cl-/HCO3- exchanger, result in chloride-rich diarrhea, a reduction in short-chain fatty acid (SCFA)-producing bacteria, and a high incidence of inflammatory bowel disease in humans and in mice. Slc26a3-/- mice are, therefore, an interesting animal model for spontaneous but mild colonic inflammation and for testing strategies to reverse or prevent the inflammation. This study investigates the effect of Escherichia coli Nissle (EcN) application on the microbiome, SCFA production, barrier integrity, and mucosal inflammation in slc26a3-/- mice. METHODS In vivo fluid absorption and bicarbonate secretion were assessed in the gut of slc26a3+/+ and slc26a3-/- mice before and during luminal perfusion with 100 mM sodium acetate. Age-matched slc26a3+/+ and slc26a3-/- mice were intragastrically gavaged twice daily with 2 × 108 CFU/100 µL of EcN for 21 days. Body weight and stool water content were assessed daily, and stool and tissues were collected for further analysis. RESULTS Addition of sodium acetate to the lumen of the proximal colon significantly increased fluid absorption and luminal alkalinization in the slc26a3-/- mice. Gavage with EcN resulted in a significant increase in SCFA levels and the expression of SCFA transporters in the slc26a3-/- cecum, the predominant habitat of EcN in mice. This was accompanied by an increase in mucus-producing goblet cells and a decrease in the expression of inflammatory markers as well as host defense antimicrobial peptides. EcN did not improve the overall diversity of the luminal microbiome but resulted in a significant increase in SCFA producers Lachnospiraceae and Ruminococcaceae in the slc26a3-/- feces. CONCLUSIONS These findings suggest that EcN is able to proliferate in the inflamed cecum, resulting in increased microbial SCFA production, decreased inflammation, and improved gut barrier properties. In sufficient dosage, probiotics may thus be an effective anti-inflammatory strategy in the diseased gut.
Collapse
Affiliation(s)
- Zhenghao Ye
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Qinghai Tan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Sabrina Woltemate
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Xinjie Tan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dorothee Römermann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Guntram A Grassl
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research DZIF, Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Marius Vital
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Ursula Seidler
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Archana Kini
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
4
|
Cherrak Y, Younes AA, Perez-Molphe-Montoya E, Maurer L, Yilmaz K, Enz U, Zeder C, Kiefer P, Christen P, Gül E, Vorholt JA, von Mering C, Hardt WD. Neutrophil recruitment during intestinal inflammation primes Salmonella elimination by commensal E. coli in a context-dependent manner. Cell Host Microbe 2025; 33:358-372.e4. [PMID: 40023150 DOI: 10.1016/j.chom.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/19/2024] [Accepted: 02/05/2025] [Indexed: 03/04/2025]
Abstract
Foodborne bacterial diarrhea involves complex pathogen-microbiota-host interactions. Pathogen-displacing probiotics are increasingly popular, but heterogeneous patient outcomes highlighted the need to understand individualized host-probiotic activity. Using the mouse gut commensal Escherichia coli 8178 and the human probiotic E. coli Nissle 1917, we found that the degree of protection against the enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm) varies across mice with distinct gut microbiotas. Pathogen clearance is linked to enteropathy severity and subsequent recruitment of intraluminal neutrophils, which differs in a microbiota-dependent manner. By combining mouse knockout and antibody-mediated depletion models with bacterial genetics, we show that neutrophils and host-derived reactive oxygen species directly influence E. coli-mediated S. Tm displacement by potentiating siderophore-bound toxin killing. Our work demonstrates how host immune factors shape pathogen-displacing probiotic efficiency while also revealing an unconventional antagonistic interaction where a gut commensal and the host synergize to displace an enteric pathogen.
Collapse
Affiliation(s)
- Yassine Cherrak
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
| | - Andrew Abi Younes
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Eugenio Perez-Molphe-Montoya
- Department of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, 8057 Zurich, Switzerland
| | - Luca Maurer
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Koray Yilmaz
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ursina Enz
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Christophe Zeder
- Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Science and Technology, 8092 Zurich, Switzerland
| | - Patrick Kiefer
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Philipp Christen
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ersin Gül
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Julia A Vorholt
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Christian von Mering
- Department of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, 8057 Zurich, Switzerland
| | - Wolf-Dietrich Hardt
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
| |
Collapse
|
|
5
|
Shah AB, Shim SH. Human microbiota peptides: important roles in human health. Nat Prod Rep 2025; 42:151-194. [PMID: 39545326 DOI: 10.1039/d4np00042k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Covering: 1974 to 2024Human microbiota consist of a diverse array of microorganisms, such as bacteria, Eukarya, archaea, and viruses, which populate various parts of the human body and live in a cooperatively beneficial relationship with the host. They play a crucial role in supporting the functional balance of the microbiome. The coevolutionary progression has led to the development of specialized metabolites that have the potential to substitute traditional antibiotics in combating global health challenges. Although there has been a lot of research on the human microbiota, there is a considerable lack of understanding regarding the wide range of peptides that these microbial populations produce. Particularly noteworthy are the antibiotics that are uniquely produced by the human microbiome, especially by bacteria, to protect against invasive infections. This review seeks to fill this knowledge gap by providing a thorough understanding of various peptides, along with their in-depth biological importance in terms of human disorders. Advancements in genomics and the understanding of molecular mechanisms that control the interactions between microbiota and hosts have made it easier to find peptides that come from the human microbiome. We hope that this review will serve as a basis for developing new therapeutic approaches and personalized healthcare strategies. Additionally, it emphasizes the significance of these microbiota in the field of natural product discovery and development.
Collapse
Affiliation(s)
- Abdul Bari Shah
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
| | - Sang Hee Shim
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
| |
Collapse
|
|
6
|
Mortzfeld BM, Bhattarai SK, Bucci V. Novel class IIb microcins show activity against Gram-negative ESKAPE and plant pathogens. eLife 2024; 13:RP102912. [PMID: 39660611 PMCID: PMC11634061 DOI: 10.7554/elife.102912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2024] Open
Abstract
Interspecies interactions involving direct competition via bacteriocin production play a vital role in shaping ecological dynamics within microbial ecosystems. For instance, the ribosomally produced siderophore bacteriocins, known as class IIb microcins, affect the colonization of host-associated pathogenic Enterobacteriaceae species. Notably, to date, only five of these antimicrobials have been identified, all derived from specific Escherichia coli and Klebsiella pneumoniae strains. We hypothesized that class IIb microcin production extends beyond these specific compounds and organisms. With a customized informatics-driven approach, screening bacterial genomes in public databases with BLAST and manual curation, we have discovered 12 previously unknown class IIb microcins in seven additional Enterobacteriaceae species, encompassing phytopathogens and environmental isolates. We introduce three novel clades of microcins (MccW, MccX, and MccZ), while also identifying eight new variants of the five known class IIb microcins. To validate their antimicrobial potential, we heterologously expressed these microcins in E. coli and demonstrated efficacy against a variety of bacterial isolates, including plant pathogens from the genera Brenneria, Gibbsiella, and Rahnella. Two newly discovered microcins exhibit activity against Gram-negative ESKAPE pathogens, i.e., Acinetobacter baumannii or Pseudomonas aeruginosa, providing the first evidence that class IIb microcins can target bacteria outside of the Enterobacteriaceae family. This study underscores that class IIb microcin genes are more prevalent in the microbial world than previously recognized and that synthetic hybrid microcins can be a viable tool to target clinically relevant drug-resistant pathogens. Our findings hold significant promise for the development of innovative engineered live biotherapeutic products tailored to combat these resilient bacteria.
Collapse
Affiliation(s)
- Benedikt M Mortzfeld
- Program in Microbiome Dynamics, University of Massachusetts Chan Medical SchoolWorcesterUnited States
- Department of Microbiology, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Shakti K Bhattarai
- Program in Microbiome Dynamics, University of Massachusetts Chan Medical SchoolWorcesterUnited States
- Department of Microbiology, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| | - Vanni Bucci
- Program in Microbiome Dynamics, University of Massachusetts Chan Medical SchoolWorcesterUnited States
- Department of Microbiology, University of Massachusetts Chan Medical SchoolWorcesterUnited States
- Program in Systems Biology, University of Massachusetts Chan Medical SchoolWorcesterUnited States
| |
Collapse
|
|
7
|
Ismael M, Huang M, Zhong Q. The Bacteriocins Produced by Lactic Acid Bacteria and the Promising Applications in Promoting Gastrointestinal Health. Foods 2024; 13:3887. [PMID: 39682959 DOI: 10.3390/foods13233887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/25/2024] [Accepted: 11/29/2024] [Indexed: 12/18/2024] Open
Abstract
Bacteriocins produced by lactic acid bacteria (LAB) are promising bioactive peptides. Intriguingly, bacteriocins have health benefits to the host and may be applied safely in the food industry as bio-preservatives or as therapeutic interventions preventing intestinal diseases. In recent years, finding a safe alternative approach to conventional treatments to promote gut health is a scientific hotspot. Therefore, this review aimed to give insight into the promising applications of LAB-bacteriocins in preventing intestinal diseases, such as colonic cancer, Helicobacter pylori infections, multidrug-resistant infection-associated colitis, viral gastroenteritis, inflammatory bowel disease, and obesity disorders. Moreover, we highlighted the recent research on bacteriocins promoting gastrointestinal health. The review also provided insights into the proposed mechanisms, challenges and opportunities, trends and prospects. In addition, a SWOT analysis was conducted on the potential applications. Based on properties, biosafety, and health functions of LAB-bacteriocins, we conclude that the future applications of LAB-bacteriocins are promising in promoting gastrointestinal health. Further in vivo trials are needed to confirm these potential effects of LAB-bacteriocins interventions.
Collapse
Affiliation(s)
- Mohamedelfatieh Ismael
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Mingxin Huang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Qingping Zhong
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China
| |
Collapse
|
|
8
|
Kulikova AV, Parker JK, Davies BW, Wilke CO. Semantic search using protein large language models detects class II microcins in bacterial genomes. mSystems 2024; 9:e0104424. [PMID: 39291976 PMCID: PMC11494933 DOI: 10.1128/msystems.01044-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 08/28/2024] [Indexed: 09/19/2024] Open
Abstract
Class II microcins are antimicrobial peptides that have shown some potential as novel antibiotics. However, to date, only 10 class II microcins have been described, and the discovery of novel microcins has been hampered by their short length and high sequence divergence. Here, we ask if we can use numerical embeddings generated by protein large language models to detect microcins in bacterial genome assemblies and whether this method can outperform sequence-based methods such as BLAST. We find that embeddings detect known class II microcins much more reliably than does BLAST and that any two microcins tend to have a small distance in embedding space even though they typically are highly diverged at the sequence level. In data sets of Escherichia coli, Klebsiella spp., and Enterobacter spp. genomes, we further find novel putative microcins that were previously missed by sequence-based search methods. IMPORTANCE Antibiotic resistance is becoming an increasingly serious problem in modern medicine, but the development pipeline for conventional antibiotics is not promising. Therefore, alternative approaches to combat bacterial infections are urgently needed. One such approach may be to employ naturally occurring antibacterial peptides produced by bacteria to kill competing bacteria. A promising class of such peptides are class II microcins. However, only a small number of class II microcins have been discovered to date, and the discovery of further such microcins has been hampered by their high sequence divergence and short length, which can cause sequence-based search methods to fail. Here, we demonstrate that a more robust method for microcin discovery can be built on the basis of a protein large language model, and we use this method to identify several putative novel class II microcins.
Collapse
Affiliation(s)
- Anastasiya V. Kulikova
- Department of Integrative Biology, The University of Texas at Austin, Austin, Texas, USA
| | - Jennifer K. Parker
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA
| | - Bryan W. Davies
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA
- John Ring LaMontagne Center for Infectious Diseases, The University of Texas at Austin, Austin, Texas, USA
| | - Claus O. Wilke
- Department of Integrative Biology, The University of Texas at Austin, Austin, Texas, USA
| |
Collapse
|
|
9
|
Wang KKA, Singh J, Albin JS, Pentelute BL, Nolan EM. Class IIb Microcin MccM Interferes with Oxidative Phosphorylation in Escherichia coli. ACS Chem Biol 2024; 19:1953-1962. [PMID: 39172990 PMCID: PMC11414533 DOI: 10.1021/acschembio.4c00226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Dysbiosis of the human gut microbiota is linked to numerous diseases. Understanding the molecular mechanisms by which microbes interact and compete with one another is required for developing successful strategies to modulate the microbiome. The natural product Microcin M (MccM) consists of a 77-residue bioactive peptide conjugated to a siderophore and is a class II microcin involved in microbial competition with an enigmatic mode-of-action. In this work, we investigated the basis for MccM activity and leveraged bioinformatics to expand the known chemical diversity of class II microcins. We applied automated fast-flow solid phase peptide synthesis coupled with chemoenzymatic chemistry to acquire MccM and demonstrated that its activity was bacteriostatic. We then used our synthetic molecule to ascertain that catecholate siderophore transporters in Escherichia coli K-12 are necessary for MccM import. Once inside the cell, we found that MccM treatment decreased the levels of intracellular ATP and interfered with gene expression. These effects were ameliorated in genetic mutants lacking ATP synthase or in conditions that support substrate-level phosphorylation. Further, we showed that MccM elevated the levels of reactive oxygen species within the target cell. We propose that MccM effects its bacteriostatic activity by decreasing the total energy level of the cell through inhibition of oxidative phosphorylation. Lastly, using genome mining, we bioinformatically identified 171 novel putative class II microcins. Our investigation sheds light on the natural processes involved in microbial competition and provides inspiration, in the form of new molecules, for future therapeutic endeavors.
Collapse
Affiliation(s)
- Kwo-Kwang Abraham Wang
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jupneet Singh
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - John S. Albin
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Bradley L. Pentelute
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Elizabeth M. Nolan
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| |
Collapse
|
|
10
|
Arnold E. Non-classical roles of bacterial siderophores in pathogenesis. Front Cell Infect Microbiol 2024; 14:1465719. [PMID: 39372500 PMCID: PMC11449898 DOI: 10.3389/fcimb.2024.1465719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Within host environments, iron availability is limited, which instigates competition for this essential trace element. In response, bacteria produce siderophores, secondary metabolites that scavenge iron and deliver it to bacterial cells via specific receptors. This role in iron acquisition contributes significantly to bacterial pathogenesis, thereby designating siderophores as virulence factors. While prior research has primarily focused on unravelling the molecular mechanisms underlying siderophore biosynthesis, uptake, and iron sequestration, recent investigations have unveiled additional non-iron chelating functions of siderophores. These emerging roles are being consistently shown to support bacterial pathogenesis. In this review, we present the current understanding of siderophores in various roles: acquiring non-iron metal ions, supporting tolerance to metal-induced and reactive oxygen species (ROS)-induced stresses, mediating siderophore signalling, inducing ROS formation, and functioning in class IIb microcins. By integrating recent findings, this review aims to provide an overview of the diverse roles of siderophores in bacterial pathogenesis.
Collapse
|
|
11
|
Mortzfeld BM, Bhattarai SK, Bucci V. Expanding the toolbox: Novel class IIb microcins show activity against Gram-negative ESKAPE and plant pathogens. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.12.05.570296. [PMID: 39253482 PMCID: PMC11383050 DOI: 10.1101/2023.12.05.570296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
Interspecies interactions involving direct competition via bacteriocin production play a vital role in shaping ecological dynamics within microbial ecosystems. For instance, the ribosomally-produced siderophore bacteriocins, known as class IIb microcins, affect the colonization of host-associated pathogenic Enterobacteriaceae species. Notably, to date, only five of these antimicrobials have been identified, all derived from specific Escherichia coli and Klebsiella pneumoniae strains. We hypothesized that class IIb microcin production extends beyond these specific compounds and organisms. With a customized informatics-driven approach, screening bacterial genomes in public databases with BLAST and manual curation, we have discovered twelve previously unknown class IIb microcins in seven additional Enterobacteriaceae species, encompassing phytopathogens and environmental isolates. We introduce three novel clades of microcins (MccW, MccX, and MccZ), while also identifying eight new variants of the five known class IIb microcins. To validate their antimicrobial potential, we heterologously expressed these microcins in E. coli and demonstrated efficacy against a variety of bacterial isolates, including plant pathogens from the genera Brenneria, Gibbsiella, and Rahnella . Two newly discovered microcins exhibit activity against Gram-negative ESKAPE pathogens, i.e. Acinetobacter baumannii or Pseudomonas aeruginosa , providing the first evidence that class IIb microcins can target bacteria outside of the Enterobacteriaceae family. This study underscores that class IIb microcin genes are more prevalent in the microbial world than previously recognized and that synthetic hybrid microcins can be a viable tool to target clinically relevant drug-resistant pathogens. Our findings hold significant promise for the development of innovative engineered live biotherapeutic products tailored to combat these resilient bacteria.
Collapse
|
|
12
|
Singh S, Koo OK. A Comprehensive Review Exploring the Protective Role of Specific Commensal Gut Bacteria against Salmonella. Pathogens 2024; 13:642. [PMID: 39204243 PMCID: PMC11356920 DOI: 10.3390/pathogens13080642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 09/03/2024] Open
Abstract
Gut microbiota is a diverse community of microorganisms that constantly work to protect the gut against pathogens. Salmonella stands out as a notorious foodborne pathogen that interacts with gut microbes, causing an imbalance in the overall composition of microbiota and leading to dysbiosis. This review focuses on the interactions between Salmonella and the key commensal bacteria such as E. coli, Lactobacillus, Clostridium, Akkermansia, and Bacteroides. The review highlights the role of these gut bacteria and their synergy in combating Salmonella through several mechanistic interactions. These include the production of siderophores, which compete with Salmonella for essential iron; the synthesis of short-chain fatty acids (SCFAs), which exert antimicrobial effects and modulate the gut environment; the secretion of bacteriocins, which directly inhibit Salmonella growth; and the modulation of cytokine responses, which influences the host's immune reaction to infection. While much research has explored Salmonella, this review aims to better understand how specific gut bacteria engage with the pathogen, revealing distinct defense mechanisms tailored to each species and how their synergy may lead to enhanced protection against Salmonella. Furthermore, the combination of these commensal bacteria could offer promising avenues for bacteria-mediated therapy during Salmonella-induced gut infections in the future.
Collapse
Affiliation(s)
| | - Ok Kyung Koo
- Department of Food Science & Technology, Chungnam National University, Daejeon 34134, Republic of Korea;
| |
Collapse
|
|
13
|
Alhubail M, McBain AJ, O'Neill CA. A survey of multiple candidate probiotic bacteria reveals specificity in the ability to modify the effects of key wound pathogens. Microbiol Spectr 2024; 12:e0034724. [PMID: 38700333 PMCID: PMC11237428 DOI: 10.1128/spectrum.00347-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/12/2024] [Indexed: 05/05/2024] Open
Abstract
We have evaluated the inhibitory effects of supernatants and lysates derived from several candidate probiotics, on the growth and biofilm formation of wound pathogens, and their ability to protect human primary epidermal keratinocytes from the toxic effects of pathogens. Supernatants (neutralized and non-neutralized) and lysates (via sonication) from Lactiplantibacillus plantarum, Limosilactobacillus reuteri, Bifidobacterium longum, Lacticaseibacillus rhamnosus GG, and Escherichia coli Nissle 1917 were tested for their inhibitory effects against Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumanni. The supernatants of L. plantarum, L. rhamnosus, B. longum, and L. rhamnosus GG reduced the growth of S. aureus, E. coli, and A. baumanni. B. longum additionally inhibited P. aeruginosa growth. However, neutralized Lactobacillus supernatants did not inhibit growth and in some cases were stimulatory. Lysates of L. plantarum and L. reuteri inhibited S. pyogenes while B. longum lysates inhibited E. coli and S. aureus growth. E. coli Nissle 1917 lysates enhanced the growth of S. pyogenes and P. aeruginosa. Biofilm formation by E. coli was reduced by lysates of L. reuteri and neutralized supernatants of all candidate probiotics. P. aeruginosa biofilm formation was reduced by E. coli Nissle supernatant but increased by L. plantarum, L. reuteri, and Bifidobacterium longum lysates. L. reuteri decreased the toxic effects of S. aureus on keratinocytes while E. coli Nissle 1917 lysates protected keratinocytes from S. pyogenes toxicity. In conclusion, lactobacilli and E. coli Nissle lysates confer inhibitory effects on pathogenic growth independently of acidification and may beneficially alter the outcome of interactions between host cell-pathogen in a species-specific manner.IMPORTANCEOne of the attributes of probiotics is their ability to inhibit pathogens. For this reason, many lactobacilli have been investigated for their effects as potential topical therapeutics against skin pathogens. However, this field is in its infancy. Even though probiotics are known to be safe when taken orally, the potential safety concerns when applied to potentially compromised skin are unknown. For this reason, we believe that extracts of probiotics will offer advantages over the use of live bacteria. In this study, we have surveyed five candidate probiotics, when used as extracts, in terms of their effects against common wound pathogens. Our data demonstrate that some probiotic extracts promote the growth of pathogens and highlight the need for careful selection of species and strains when probiotics are to be used topically.
Collapse
Affiliation(s)
- Muna Alhubail
- Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom
| | - Andrew J. McBain
- Faculty of Biology, School of Health Sciences, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Catherine A. O'Neill
- Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom
| |
Collapse
|
|
14
|
Zhao Y, Ding WJ, Xu L, Sun JQ. A comprehensive comparative genomic analysis revealed that plant growth promoting traits are ubiquitous in strains of Stenotrophomonas. Front Microbiol 2024; 15:1395477. [PMID: 38817968 PMCID: PMC11138164 DOI: 10.3389/fmicb.2024.1395477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/29/2024] [Indexed: 06/01/2024] Open
Abstract
Stenotrophomonas strains, which are often described as plant growth promoting (PGP) bacteria, are ubiquitous in many environments. A total of 213 genomes of strains of Stenotrophomonas were analyzed using comparative genomics to better understand the ecological roles of these bacteria in the environment. The pan-genome of the 213 strains of Stenotrophomonas consists of 27,186 gene families, including 710 core gene families, 11,039 unique genes and 15,437 accessory genes. Nearly all strains of Stenotrophomonas harbor the genes for GH3-family cellulose degradation and GH2- and GH31-family hemicellulose hydrolase, as well as intact glycolysis and tricarboxylic acid cycle pathways. These abilities suggest that the strains of this genus can easily obtain carbon and energy from the environment. The Stenotrophomonas strains can respond to oxidative stress by synthesizing catalase, superoxide dismutase, methionine sulfoxide reductase, and disulfide isomerase, as well as managing their osmotic balance by accumulating potassium and synthesizing compatible solutes, such as betaine, trehalose, glutamate, and proline. Each Stenotrophomonas strain also contains many genes for resistance to antibiotics and heavy metals. These genes that mediate stress tolerance increase the ability of Stenotrophomonas strains to survive in extreme environments. In addition, many functional genes related to attachment and plant colonization, growth promotion and biocontrol were identified. In detail, the genes associated with flagellar assembly, motility, chemotaxis and biofilm formation enable the strains of Stenotrophomonas to effectively colonize host plants. The presence of genes for phosphate-solubilization and siderophore production and the polyamine, indole-3-acetic acid, and cytokinin biosynthetic pathways confer the ability to promote plant growth. These strains can produce antimicrobial compounds, chitinases, lipases and proteases. Each Stenotrophomonas genome contained 1-9 prophages and 17-60 genomic islands, and the genes related to antibiotic and heavy metal resistance and the biosynthesis of polyamines, indole-3-acetic acid, and cytokinin may be acquired by horizontal gene transfer. This study demonstrates that strains of Stenotrophomonas are highly adaptable for different environments and have strong potential for use as plant growth-promoting bacteria.
Collapse
Affiliation(s)
- Yang Zhao
- Lab for Microbial Resources, School of Ecology and Environment, Inner Mongolia University, Hohhot, China
| | - Wen-Jing Ding
- Lab for Microbial Resources, School of Ecology and Environment, Inner Mongolia University, Hohhot, China
| | - Lian Xu
- Jiangsu Key Lab for Organic Solid Waste Utilization, Educational Ministry Engineering Center of Resource-saving Fertilizers, Jiangsu Collaborative Innovation Center for Solid Organic Waste Resource Utilization, Nanjing Agricultural University, Nanjing, China
| | - Ji-Quan Sun
- Lab for Microbial Resources, School of Ecology and Environment, Inner Mongolia University, Hohhot, China
| |
Collapse
|
|
15
|
Jirillo E, Palmirotta R, Colella M, Santacroce L. A Bird's-Eye View of the Pathophysiologic Role of the Human Urobiota in Health and Disease: Can We Modulate It? PATHOPHYSIOLOGY 2024; 31:52-67. [PMID: 38390942 PMCID: PMC10885084 DOI: 10.3390/pathophysiology31010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/24/2024] Open
Abstract
For a long time, urine has been considered sterile in physiological conditions, thanks to the particular structure of the urinary tract and the production of uromodulin or Tamm-Horsfall protein (THP) by it. More recently, thanks to the development and use of new technologies, i.e., next-generation sequencing and expanded urine culture, the identification of a microbial community in the urine, the so-called urobiota, became possible. Major phyla detected in the urine are represented by Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Particularly, the female urobiota is largely represented by Lactobacillus spp., which are very active against urinary pathogenic Escherichia (E.) coli (UPEC) strains via the generation of lactic acid and hydrogen peroxide. Gut dysbiosis accounts for recurrent urinary tract infections (UTIs), so-called gut-bladder axis syndrome with the formation of intracellular bacterial communities in the course of acute cystitis. However, other chronic urinary tract infections are caused by bacterial strains of intestinal derivation. Monomicrobial and polymicrobial infections account for the outcome of acute and chronic UTIs, even including prostatitis and chronic pelvic pain. E. coli isolates have been shown to be more invasive and resistant to antibiotics. Probiotics, fecal microbial transplantation, phage therapy, antimicrobial peptides, and immune-mediated therapies, even including vaccines for the treatment of UTIs, will be described.
Collapse
Affiliation(s)
- Emilio Jirillo
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.J.); (R.P.); (L.S.)
| | - Raffaele Palmirotta
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.J.); (R.P.); (L.S.)
| | - Marica Colella
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.J.); (R.P.); (L.S.)
- Doctoral School, eCampus University, 22060 Novedrate, Italy
| | - Luigi Santacroce
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.J.); (R.P.); (L.S.)
| |
Collapse
|
|
16
|
Delavy M, Sertour N, d'Enfert C, Bougnoux ME. Metagenomics and metabolomics approaches in the study of Candida albicans colonization of host niches: a framework for finding microbiome-based antifungal strategies. Trends Microbiol 2023; 31:1276-1286. [PMID: 37652786 DOI: 10.1016/j.tim.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/16/2023] [Accepted: 08/02/2023] [Indexed: 09/02/2023]
Abstract
In silico and experimental approaches have allowed an ever-growing understanding of the interactions within the microbiota. For instance, recently acquired data have increased knowledge of the mechanisms that support, in the gut and vaginal microbiota, the resistance to colonization by Candida albicans, an opportunistic fungal pathogen whose overgrowth can initiate severe infections in immunocompromised patients. Here, we review how bacteria from the microbiota interact with C. albicans. We show how recent OMICs-based pipelines, using metagenomics and/or metabolomics, have identified bacterial species and metabolites modulating C. albicans growth. We finally discuss how the combined use of cutting-edge OMICs-based and experimental approaches could provide new means to control C. albicans overgrowth within the microbiota and prevent its consequences.
Collapse
Affiliation(s)
- Margot Delavy
- Institut Pasteur, Université Paris Cité, INRAE USC2019, Unité Biologie et Pathogénicité Fongiques, Paris, France
| | - Natacha Sertour
- Institut Pasteur, Université Paris Cité, INRAE USC2019, Unité Biologie et Pathogénicité Fongiques, Paris, France
| | - Christophe d'Enfert
- Institut Pasteur, Université Paris Cité, INRAE USC2019, Unité Biologie et Pathogénicité Fongiques, Paris, France
| | - Marie-Elisabeth Bougnoux
- Institut Pasteur, Université Paris Cité, INRAE USC2019, Unité Biologie et Pathogénicité Fongiques, Paris, France; Assistance Publique des Hôpitaux de Paris (APHP), Hôpital Necker-Enfants-Malades, Unité de Parasitologie-Mycologie, Service de Microbiologie Clinique, Paris, France.
| |
Collapse
|
|
17
|
Effendi SSW, Ng IS. Prospective and challenges of live bacterial therapeutics from a superhero Escherichia coli Nissle 1917. Crit Rev Microbiol 2023; 49:611-627. [PMID: 35947523 DOI: 10.1080/1040841x.2022.2109405] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 07/02/2022] [Accepted: 08/01/2022] [Indexed: 11/03/2022]
Abstract
Escherichia coli Nissle 1917 (EcN), the active component of Mutaflor(R), is a notable probiotic from Gram-negative to treat Crohn's disease and irritable bowel syndrome. Therefore, a comprehensive genomic database maximizes the systemic probiotic assessment to discover EcN's role in human health. Recently, advanced synthetic and genetic tools have opened up a rich area to execute EcN as "living medicines" with controllable functions. Incorporating unique biomarkers allows the engineered EcN to switch genes on and off in response to environmental cues. Since EcN holds promise as a safe nature vehicle, more studies are desired to fully realize a wide range of probiotic potential for disease treatment. This review aims to deliver a historical origin of EcN, discuss the recent promising genetic toolbox in the rational design of probiotics, and pinpoint the clinical translation and evaluation of engineered EcN in vitro and in vivo. The summary of safety concerns, strategies of biotherapeutics development, and the challenges and prospects of engineered EcN is also concluded.
Collapse
Affiliation(s)
| | - I-Son Ng
- Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan
| |
Collapse
|
|
18
|
Rebai Y, Wagner L, Gnaien M, Hammer ML, Kapitan M, Niemiec MJ, Mami W, Mosbah A, Messadi E, Mardassi H, Vylkova S, Jacobsen ID, Znaidi S. Escherichia coli Nissle 1917 Antagonizes Candida albicans Growth and Protects Intestinal Cells from C. albicans-Mediated Damage. Microorganisms 2023; 11:1929. [PMID: 37630490 PMCID: PMC10457924 DOI: 10.3390/microorganisms11081929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 08/27/2023] Open
Abstract
Candida albicans is a pathobiont of the gastrointestinal tract. It can contribute to the diversity of the gut microbiome without causing harmful effects. When the immune system is compromised, C. albicans can damage intestinal cells and cause invasive disease. We hypothesize that a therapeutic approach against C. albicans infections can rely on the antimicrobial properties of probiotic bacteria. We investigated the impact of the probiotic strain Escherichia coli Nissle 1917 (EcN) on C. albicans growth and its ability to cause damage to intestinal cells. In co-culture kinetic assays, C. albicans abundance gradually decreased over time compared with C. albicans abundance in the absence of EcN. Quantification of C. albicans survival suggests that EcN exerts a fungicidal activity. Cell-free supernatants (CFS) collected from C. albicans-EcN co-culture mildly altered C. albicans growth, suggesting the involvement of an EcN-released compound. Using a model of co-culture in the presence of human intestinal epithelial cells, we further show that EcN prevents C. albicans from damaging enterocytes both distantly and through direct contact. Consistently, both C. albicans's filamentous growth and microcolony formation were altered by EcN. Taken together, our study proposes that probiotic-strain EcN can be exploited for future therapeutic approaches against C. albicans infections.
Collapse
Affiliation(s)
- Yasmine Rebai
- Laboratoire de Microbiologie Moléculaire, Vaccinologie et Développement Biotechnologique (LR16IPT01), Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1068, Tunisia; (Y.R.)
| | - Lysett Wagner
- Septomics Research Center, Friedrich Schiller University, 07745 Jena, Germany
- Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, 07745 Jena, Germany
| | - Mayssa Gnaien
- Laboratoire de Microbiologie Moléculaire, Vaccinologie et Développement Biotechnologique (LR16IPT01), Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1068, Tunisia; (Y.R.)
| | - Merle L. Hammer
- Septomics Research Center, Friedrich Schiller University, 07745 Jena, Germany
- Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, 07745 Jena, Germany
| | - Mario Kapitan
- Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, 07745 Jena, Germany
- Center for Sepsis Control and Care, 07747 Jena, Germany
| | - Maria Joanna Niemiec
- Septomics Research Center, Friedrich Schiller University, 07745 Jena, Germany
- Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, 07745 Jena, Germany
| | - Wael Mami
- Plateforme de Physiologie et Physiopathologie Cardiovasculaires (P2C), Laboratoire des Biomolécules, Venins et Applications Théranostiques (LR20IPT01), Institut Pasteur de Tunis, Université Tunis El Manar, Tunis 1068, Tunisia
| | - Amor Mosbah
- Laboratory of Biotechnology and Bio-Geo Resources Valorization (LR11ES31), Higher Institute of Biotechnology of Sidi Thabet (ISBST), University of Manouba, Tunis 2010, Tunisia
| | - Erij Messadi
- Plateforme de Physiologie et Physiopathologie Cardiovasculaires (P2C), Laboratoire des Biomolécules, Venins et Applications Théranostiques (LR20IPT01), Institut Pasteur de Tunis, Université Tunis El Manar, Tunis 1068, Tunisia
| | - Helmi Mardassi
- Laboratoire de Microbiologie Moléculaire, Vaccinologie et Développement Biotechnologique (LR16IPT01), Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1068, Tunisia; (Y.R.)
| | - Slavena Vylkova
- Septomics Research Center, Friedrich Schiller University, 07745 Jena, Germany
- Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, 07745 Jena, Germany
| | - Ilse D. Jacobsen
- Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute, 07745 Jena, Germany
- Center for Sepsis Control and Care, 07747 Jena, Germany
- Institute of Microbiology, Friedrich Schiller University, 07743 Jena, Germany
| | - Sadri Znaidi
- Laboratoire de Microbiologie Moléculaire, Vaccinologie et Développement Biotechnologique (LR16IPT01), Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1068, Tunisia; (Y.R.)
- Institut Pasteur, Institut National de la Recherche Agronomique (INRA), Département Mycologie, Unité Biologie et Pathogénicité Fongiques, 75015 Paris, France
| |
Collapse
|
|
19
|
Ma Y, Fu W, Hong B, Wang X, Jiang S, Wang J. Antibacterial MccM as the Major Microcin in Escherichia coli Nissle 1917 against Pathogenic Enterobacteria. Int J Mol Sci 2023; 24:11688. [PMID: 37511446 PMCID: PMC10380612 DOI: 10.3390/ijms241411688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Probiotic Escherichia coli Nissle 1917 (EcN) possesses excellent antibacterial effects on pathogenic enterobacteria. The microcins MccM and MccH47 produced in EcN played critical roles, but they are understudied and poorly characterized, and the individual antibacterial mechanisms are still unclear. In this study, three EcN mutants (ΔmcmA, ΔmchB, and ΔmcmAΔmchB) were constructed and compared with wild-type EcN (EcN wt) to test for inhibitory effects on the growth of Escherichia coli O157: H7, Salmonella enterica (SE), and Salmonella typhimurium (ST). The antibacterial effects on O157: H7 were not affected by the knockout of mcmA (MccM) and mchB (MccH47) in EcN. However, the antibacterial effect on Salmonella declined sharply in EcN mutants ΔmcmA. The overexpressed mcmA gene in EcN::mcmA showed more efficient antibacterial activity on Salmonella than that of EcN wt. Furthermore, the EcN::mcmA strain significantly reduced the abilities of adhesion and invasion of Salmonella to intestinal epithelial cells, decreasing the invasion ability of ST by 56.31% (62.57 times more than that of EcN wt) while reducing the adhesion ability of ST by 50.14% (2.41 times more than that of EcN wt). In addition, the supernatant of EcN::mcmA culture significantly decreased the mRNA expression and secretion of IL-1β, TNF-α, and IL-6 on macrophages induced by LPS. The EcN::mcmA strain generated twice as much orange halo as EcN wt by CAS agar diffusion assay by producing more siderophores. MccM was more closely related to the activity of EcN against Salmonella, and MccM-overproducing EcN inhibited Salmonella growth by producing more siderophores-MccM to compete for iron, which was critical to pathogen growth. Based on the above, EcN::mcmA can be developed as engineered probiotics to fight against pathogenic enterobacteria colonization in the gut.
Collapse
Affiliation(s)
- Yi Ma
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
- Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China
| | - Wei Fu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Bin Hong
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Xinfeng Wang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Shoujin Jiang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Jufang Wang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| |
Collapse
|
|
20
|
Bisaro F, Shuman HA, Feldman MF, Gebhardt MJ, Pukatzki S. Acinetobacter baumannii ATCC 17978 encodes a microcin system with antimicrobial properties for contact-independent competition. MICROBIOLOGY (READING, ENGLAND) 2023; 169:001346. [PMID: 37289493 PMCID: PMC10333792 DOI: 10.1099/mic.0.001346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/25/2023] [Indexed: 06/09/2023]
Abstract
Acinetobacter baumannii is a multidrug-resistant opportunistic pathogen that persists in the hospital environment and causes various clinical infections, primarily affecting immunocompromised patients. A. baumannii has evolved a wide range of mechanisms to compete with neighbouring bacteria. One such competition strategy depends on small secreted peptides called microcins, which exert antimicrobial effects in a contact-independent manner. Here, we report that A. baumannii ATCC 17978 (AB17978) encodes the class II microcin 17 978 (Mcc17978) with antimicrobial activity against closely related Acinetobacter, and surprisingly, also Escherichia coli strains. We identified the genetic locus encoding the Mcc17978 system in AB17978. Using classical bacterial genetic approaches, we determined that the molecular receptor of Mcc17978 in E. coli is the iron-catecholate transporter Fiu, and in Acinetobacter is Fiu's homolog, PiuA. In bacteria, the Ferric uptake regulator (Fur) positively regulates siderophore systems and microcin systems under iron-deprived environments. We found that the Mcc17978 system is upregulated under low-iron conditions commonly found in the host environment and identified a putative Fur binding site upstream of the mcc17978 gene. When we tested the antimicrobial activity of Mcc17978 under different levels of iron availability, we observed that low iron levels not only triggered transcriptional induction of the microcin, but also led to enhanced microcin activity. Taken together, our findings suggest that A. baumannii may utilize microcins to compete with other microbes for resources during infection.
Collapse
Affiliation(s)
- Fabiana Bisaro
- Department of Biology, The City College, City University of New York, New York, NY 10031, USA
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis MO 63110, USA
| | - Howard A. Shuman
- Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA
- Present address: P.O. Box 1088, Sheffield, MA 01257, USA
| | - Mario F. Feldman
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis MO 63110, USA
| | - Michael J. Gebhardt
- Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa 52242, USA
| | - Stefan Pukatzki
- Department of Biology, The City College, City University of New York, New York, NY 10031, USA
| |
Collapse
|
|
21
|
Kirundi J, Moghadamrad S, Urbaniak C. Microbiome-liver crosstalk: A multihit therapeutic target for liver disease. World J Gastroenterol 2023; 29:1651-1668. [PMID: 37077519 PMCID: PMC10107210 DOI: 10.3748/wjg.v29.i11.1651] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/05/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
Liver disease has become a leading cause of death, particularly in the West, where it is attributed to more than two million deaths annually. The correlation between gut microbiota and liver disease is still not fully understood. However, it is well known that gut dysbiosis accompanied by a leaky gut causes an increase in lipopolysaccharides in circulation, which in turn evoke massive hepatic inflammation promoting liver cirrhosis. Microbial dysbiosis also leads to poor bile acid metabolism and low short-chain fatty acids, all of which exacerbate the inflammatory response of liver cells. Gut microbial homeostasis is maintained through intricate processes that ensure that commensal microbes adapt to the low oxygen potential of the gut and that they rapidly occupy all the intestinal niches, thus outcompeting any potential pathogens for available nutrients. The crosstalk between the gut microbiota and its metabolites also guarantee an intact gut barrier. These processes that protect against destabilization of gut microbes by potential entry of pathogenic bacteria are collectively called colonization resistance and are equally essential for liver health. In this review, we shall investigate how the mechanisms of colonization resistance influence the liver in health and disease and the microbial-liver crosstalk potential as therapeutic target areas.
Collapse
Affiliation(s)
- Jorum Kirundi
- Department of Biomedical Research, University of Bern, Bern 3014, Switzerland
| | - Sheida Moghadamrad
- Department of Gastroenterology/Hepatology, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona and Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano 6900, Switzerland
| | | |
Collapse
|
|
22
|
Abstract
Microcins are a class of antimicrobial peptides produced by certain Gram-negative bacterial species to kill or inhibit the growth of competing bacteria. Only 10 unique, experimentally validated class II microcins have been identified, and the majority of these come from Escherichia coli. Although the current representation of microcins is sparse, they exhibit a diverse array of molecular functionalities, uptake mechanisms, and target specificities. This broad diversity from such a small representation suggests that microcins may have untapped potential for bioprospecting peptide antibiotics from genomic data sets. We used a systematic bioinformatics approach to search for verified and novel class II microcins in E. coli and other species within its family, Enterobacteriaceae. Nearly one-quarter of the E. coli genome assemblies contained one or more microcins, where the prevalence of hits to specific microcins varied by isolate phylogroup. E. coli isolates from human extraintestinal and poultry meat sources were enriched for microcins, while those from freshwater were depleted. Putative microcins were found in various abundances across all five distinct phylogenetic lineages of Enterobacteriaceae, with a particularly high prevalence in the "Klebsiella" clade. Representative genome assemblies from species across the Enterobacterales order, as well as a few outgroup species, also contained putative microcin sequences. This study suggests that microcins have a complicated evolutionary history, spanning far beyond our limited knowledge of the currently validated microcins. Efforts to functionally characterize these newly identified microcins have great potential to open a new field of peptide antibiotics and microbiome modulators and elucidate the ways in which bacteria compete with each other. IMPORTANCE Class II microcins are small bacteriocins produced by strains of Gram-negative bacteria in the Enterobacteriaceae. They are generally understood to play a role in interbacterial competition, although direct evidence of this is limited, and they could prove informative in developing new peptide antibiotics. However, few examples of verified class II microcins exist, and novel microcins are difficult to identify due to their sequence diversity, making it complicated to study them as a group. Here, we overcome this limitation by developing a bioinformatics pipeline to detect microcins in silico. Using this pipeline, we demonstrate that both verified and novel class II microcins are widespread within and outside the Enterobacteriaceae, which has not been systematically shown previously. The observed prevalence of class II microcins suggests that they are ecologically important, and the elucidation of novel microcins provides a resource that can be used to expand our knowledge of the structure and function of microcins as antibacterials.
Collapse
|
|
23
|
Suryaletha K, Savithri AV, Nayar SA, Asokan S, Rajeswary D, Thomas S. Demystifying Bacteriocins of Human Microbiota by Genome Guided Prospects: An Impetus to Rekindle the Antimicrobial Research. Curr Protein Pept Sci 2022; 23:811-822. [PMID: 36278460 DOI: 10.2174/1389203724666221019111515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/14/2022] [Accepted: 09/06/2022] [Indexed: 11/07/2022]
Abstract
The human microbiome is a reservoir of potential bacteriocins that can counteract multidrug resistant bacterial pathogens. Unlike antibiotics, bacteriocins selectively inhibit a spectrum of competent bacteria and are said to safeguard gut commensals, reducing the chance of dysbiosis. Bacteriocinogenic probiotics or bacteriocins of human origin will be more pertinent in human physiological conditions for therapeutic applications to act against invading pathogens. Recent advancement in the omics approach enables the mining of diverse and novel bacteriocins by identifying biosynthetic gene clusters from the human microbial genome, pangenome or shotgun metagenome, which is a breakthrough in the discovery line of novel bacteriocins. This review summarizes the most recent trends and therapeutic potential of bacteriocins of human microbial origin, the advancement in the in silico algorithms and databases in the discovery of novel bacteriocin, and how to bridge the gap between the discovery of bacteriocin genes from big datasets and their in vitro production. Besides, the later part of the review discussed the various impediments in their clinical applications and possible solution to bring them into the frontline therapeutics to control infections, thereby meeting the challenges of global antimicrobial resistance.
Collapse
Affiliation(s)
- Karthika Suryaletha
- Cholera & Biofilm Research Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Akhila Velappan Savithri
- Cholera & Biofilm Research Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Seema A Nayar
- Department of Microbiology, Government Medical College, Thiruvananthapuram, Kerala, India
| | - Sijo Asokan
- Cholera & Biofilm Research Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Divya Rajeswary
- Cholera & Biofilm Research Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Sabu Thomas
- Cholera & Biofilm Research Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| |
Collapse
|
|
24
|
Ongpipattanakul C, Desormeaux EK, DiCaprio A, van der Donk WA, Mitchell DA, Nair SK. Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides. Chem Rev 2022; 122:14722-14814. [PMID: 36049139 PMCID: PMC9897510 DOI: 10.1021/acs.chemrev.2c00210] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a natural product class that has undergone significant expansion due to the rapid growth in genome sequencing data and recognition that they are made by biosynthetic pathways that share many characteristic features. Their mode of actions cover a wide range of biological processes and include binding to membranes, receptors, enzymes, lipids, RNA, and metals as well as use as cofactors and signaling molecules. This review covers the currently known modes of action (MOA) of RiPPs. In turn, the mechanisms by which these molecules interact with their natural targets provide a rich set of molecular paradigms that can be used for the design or evolution of new or improved activities given the relative ease of engineering RiPPs. In this review, coverage is limited to RiPPs originating from bacteria.
Collapse
Affiliation(s)
- Chayanid Ongpipattanakul
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Emily K. Desormeaux
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Adam DiCaprio
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Wilfred A. van der Donk
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
| | - Douglas A. Mitchell
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Microbiology, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
| | - Satish K. Nair
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
| |
Collapse
|
|
25
|
Palmer JD, Foster KR. The evolution of spectrum in antibiotics and bacteriocins. Proc Natl Acad Sci U S A 2022; 119:e2205407119. [PMID: 36099299 PMCID: PMC9499554 DOI: 10.1073/pnas.2205407119] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/05/2022] [Indexed: 12/02/2022] Open
Abstract
A key property of many antibiotics is that they will kill or inhibit a diverse range of microbial species. This broad-spectrum of activity has its evolutionary roots in ecological competition, whereby bacteria and other microbes use antibiotics to suppress other strains and species. However, many bacteria also use narrow-spectrum toxins, such as bacteriocins, that principally target conspecifics. Why has such a diversity in spectrum evolved? Here, we develop an evolutionary model to understand antimicrobial spectrum. Our first model recapitulates the intuition that broad-spectrum is best, because it enables a microbe to kill a wider diversity of competitors. However, this model neglects an important property of antimicrobials: They are commonly bound, sequestered, or degraded by the cells they target. Incorporating this toxin loss reveals a major advantage to narrow-spectrum toxins: They target the strongest ecological competitor and avoid being used up on less important species. Why then would broad-spectrum toxins ever evolve? Our model predicts that broad-spectrum toxins will be favored by natural selection if a strain is highly abundant and can overpower both its key competitor and other species. We test this prediction by compiling and analyzing a database of the regulation and spectrum of toxins used in inter-bacterial competition. This analysis reveals a strong association between broad-spectrum toxins and density-dependent regulation, indicating that they are indeed used when strains are abundant. Our work provides a rationale for why bacteria commonly evolve narrow-spectrum toxins such as bacteriocins and suggests that the evolution of antibiotics proper is a signature of ecological dominance.
Collapse
Affiliation(s)
- Jacob D. Palmer
- Department of Biology, University of Oxford, Oxford, OX1 3RB, United Kingdom
- Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom
| | - Kevin R. Foster
- Department of Biology, University of Oxford, Oxford, OX1 3RB, United Kingdom
- Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom
| |
Collapse
|
|
26
|
Marković KG, Grujović MŽ, Koraćević MG, Nikodijević DD, Milutinović MG, Semedo-Lemsaddek T, Djilas MD. Colicins and Microcins Produced by Enterobacteriaceae: Characterization, Mode of Action, and Putative Applications. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:11825. [PMID: 36142096 PMCID: PMC9517006 DOI: 10.3390/ijerph191811825] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/12/2022] [Accepted: 09/15/2022] [Indexed: 06/15/2023]
Abstract
Enterobacteriaceae are widely present in many environments related to humans, including the human body and the food that they consume, from both plant or animal origin. Hence, they are considered relevant members of the gastrointestinal tract microbiota. On the other hand, these bacteria are also recognized as putative pathogens, able to impair human health and, in food, they are considered indicators for the microbiological quality and hygiene status of a production process. Nevertheless, beneficial properties have also been associated with Enterobacteriaceae, such as the ability to synthesize peptides and proteins, which can have a role in the structure of microbial communities. Among these antimicrobial molecules, those with higher molecular mass are called colicins, while those with lower molecular mass are named microcins. In recent years, some studies show an emphasis on molecules that can help control the development of pathogens. However, not enough data are available on this subject, especially related to microcins. Hence, this review gathers and summarizes current knowledge on colicins and microcins, potential usage in the treatment of pathogen-associated diseases and cancer, as well as putative applications in food biotechnology.
Collapse
Affiliation(s)
- Katarina G. Marković
- Institute for Information Technologies, Department of Science, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia
| | - Mirjana Ž. Grujović
- Institute for Information Technologies, Department of Science, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia
| | - Maja G. Koraćević
- Innovation Center, University of Niš, 18000 Niš, Serbia
- Faculty of Medicine, Department of Pharmacy, University of Niš, 18000 Niš, Serbia
| | - Danijela D. Nikodijević
- Faculty of Science, Department of Biology and Ecology, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia
| | - Milena G. Milutinović
- Faculty of Science, Department of Biology and Ecology, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia
| | - Teresa Semedo-Lemsaddek
- CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Milan D. Djilas
- Institute for Public Health of Vojvodina, Futoška 121, 21000 Novi Sad, Serbia
| |
Collapse
|
|
27
|
Serapio-Palacios A, Woodward SE, Vogt SL, Deng W, Creus-Cuadros A, Huus KE, Cirstea M, Gerrie M, Barcik W, Yu H, Finlay BB. Type VI secretion systems of pathogenic and commensal bacteria mediate niche occupancy in the gut. Cell Rep 2022; 39:110731. [PMID: 35476983 DOI: 10.1016/j.celrep.2022.110731] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 02/04/2022] [Accepted: 04/01/2022] [Indexed: 12/18/2022] Open
Abstract
The type VI secretion system (T6SS) is a contractile nanomachine widely distributed among pathogenic and commensal Gram-negative bacteria. The T6SS is used for inter-bacterial competition to directly kill competing species; however, its importance during bacterial infection in vivo remains poorly understood. We report that the murine pathogen Citrobacter rodentium, used as a model for human pathogenic Escherichia coli, harbors two functional T6SSs. C. rodentium employs its T6SS-1 to colonize the murine gastrointestinal tract by targeting commensal Enterobacteriaceae. We identify VgrG1 as a C. rodentium T6SS antibacterial effector, which exhibits toxicity in E. coli. Conversely, commensal prey species E. coli Mt1B1 employs two T6SSs of its own to counter C. rodentium colonization. Collectively, these data demonstrate that the T6SS is a potent weapon during bacterial competition and is used by both invading pathogens and resident microbiota to fight for a niche in the hostile gut environment.
Collapse
Affiliation(s)
- Antonio Serapio-Palacios
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada
| | - Sarah E Woodward
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada
| | - Stefanie L Vogt
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada
| | - Wanyin Deng
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Anna Creus-Cuadros
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada
| | - Kelsey E Huus
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada
| | - Mihai Cirstea
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada
| | - Madeleine Gerrie
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Weronika Barcik
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada
| | - Hongbing Yu
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - B Brett Finlay
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, BC V6T 1Z3, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
| |
Collapse
|
|
28
|
Parker JK, Davies BW. Microcins reveal natural mechanisms of bacterial manipulation to inform therapeutic development. MICROBIOLOGY (READING, ENGLAND) 2022; 168:001175. [PMID: 35438625 PMCID: PMC10233263 DOI: 10.1099/mic.0.001175] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/17/2022] [Indexed: 12/20/2022]
Abstract
Microcins are an understudied and poorly characterized class of antimicrobial peptides. Despite the existence of only 15 examples, all identified from the Enterobacteriaceae, microcins display diversity in sequence, structure, target cell uptake, cytotoxic mechanism of action and target specificity. Collectively, these features describe some of the unique means nature has contrived for molecules to cross the 'impermeable' barrier of the Gram-negative bacterial outer membrane and inflict cytotoxic effects. Microcins appear to be widely dispersed among different species and in different environments, where they function in regulating microbial communities in diverse ways, including through competition. Growing evidence suggests that microcins may be adapted for therapeutic uses such as antimicrobial drugs, microbiome modulators or facilitators of peptide uptake into cells. Advancing our biological, ecological and biochemical understanding of the roles of microcins in bacterial interactions, and learning how to regulate and modify microcin activity, is essential to enable such therapeutic applications.
Collapse
Affiliation(s)
| | - Bryan William Davies
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA
- John Ring LaMontagne Center for Infectious Diseases, The University of Texas at Austin, Austin, Texas, USA
| |
Collapse
|
|
29
|
Kenneally C, Murphy CP, Sleator RD, Culligan EP. The Urinary Microbiome and Biological Therapeutics: Novel Therapies For Urinary Tract Infections. Microbiol Res 2022; 259:127010. [DOI: 10.1016/j.micres.2022.127010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 12/12/2022]
|
|
30
|
Geervliet M, de Vries H, Jansen CA, Rutten VPMG, van Hees H, Wen C, Skovgaard K, Antonello G, Savelkoul HFJ, Smidt H, Tijhaar E, Wells JM. Effects of E scherichia coli Nissle 1917 on the Porcine Gut Microbiota, Intestinal Epithelium and Immune System in Early Life. Front Microbiol 2022; 13:842437. [PMID: 35283814 PMCID: PMC8914288 DOI: 10.3389/fmicb.2022.842437] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/01/2022] [Indexed: 12/22/2022] Open
Abstract
Early in life and particularly around weaning, piglets are susceptible to infections because of abrupt social, environmental, and dietary changes. Dietary interventions with probiotic bacteria have gained popularity because of the increased awareness of the direct link between diet and health. In this study, piglets received the probiotic strain Escherichia coli Nissle 1917 (EcN) or a control treatment perorally from day 2 after birth until 2 weeks post-weaning. To investigate spatio-temporal effects of EcN on the gut microbiota composition, intestinal epithelial gene expression and immune system, feces, digesta, blood, scraping material and mesenteric lymph node tissue were collected at different time points. In addition, oral vaccinations against Salmonella enterica serovar Typhimurium were administered on days 21 and 45 of the study to assess the immunocompetence. EcN-treated pigs showed a reduced diversity of taxa within the phylum Proteobacteria and a lower relative abundance of taxa within the genus Treponema during the pre-weaning period. Moreover, EcN induced T cell proliferation and Natural Killer cell activation in blood and enhanced IL-10 production in ex vivo stimulated mesenteric lymph node cells, the latter pointing toward a more regulatory or anti-inflammatory state of the local gut-associated immune system. These outcomes were primarily observed pre-weaning. No significant differences were observed between the treatment groups with regards to body weight, epithelial gene expression, and immune response upon vaccination. Differences observed during the post-weaning period between the treatment groups were modest. Overall, this study demonstrates that the pre-weaning period offers a 'window of opportunity' to modulate the porcine gut microbiota and immune system through dietary interventions such as EcN supplementation.
Collapse
Affiliation(s)
- Mirelle Geervliet
- Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands
| | - Hugo de Vries
- Host-Microbe Interactomics Group, Wageningen University & Research, Wageningen, Netherlands
- Laboratory of Microbiology, Wageningen University & Research, Wageningen, Netherlands
| | - Christine A. Jansen
- Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands
| | - Victor P. M. G. Rutten
- Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
- Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa
| | - Hubèrt van Hees
- Research and Development, Trouw Nutrition, Amersfoort, Netherlands
| | - Caifang Wen
- Laboratory of Microbiology, Wageningen University & Research, Wageningen, Netherlands
| | - Kerstin Skovgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Giacomo Antonello
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Huub F. J. Savelkoul
- Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands
| | - Hauke Smidt
- Laboratory of Microbiology, Wageningen University & Research, Wageningen, Netherlands
| | - Edwin Tijhaar
- Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands
| | - Jerry M. Wells
- Host-Microbe Interactomics Group, Wageningen University & Research, Wageningen, Netherlands
| |
Collapse
|
|
31
|
Yu H, Shang L, Yang G, Dai Z, Zeng X, Qiao S. Biosynthetic Microcin J25 Exerts Strong Antibacterial, Anti-Inflammatory Activities, Low Cytotoxicity Without Increasing Drug-Resistance to Bacteria Target. Front Immunol 2022; 13:811378. [PMID: 35250983 PMCID: PMC8894198 DOI: 10.3389/fimmu.2022.811378] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/27/2022] [Indexed: 12/15/2022] Open
Abstract
Multidrug resistant (MDR) bacterial infection has emerged, raising concerns about untreatable infections, and posing the highest health risks. Antimicrobial peptides (AMPs) are thought to be the best remedy for this problem. Here, we showed biosynthetic microcin J25 (MccJ25) exhibited excellent bactericidal activity against standard and clinically relevant veterinary MDR strains with high stability, no cytotoxicity, and no increase in drug resistance. Analysis of antimicrobial mechanism possessed by sensitive enterotoxigenic Escherichia coli (ETEC) based on electron microscopy and Sytox Green methods was carried out. Results showed excellent activity against ETEC was due to permeabilizing bacterial membranes and strong affinity. MccJ25 exhibited high endotoxin-neutralizing activity in both in vivo and in vitro environments, and mice exposed to lipopolysaccharide (LPS) showed decreased plasma LPS levels and improved survival after administration of MccJ25. In an LPS-treated mouse septicemia model, MccJ25 treatment significantly alleviated inflammatory responses by inhibiting proinflammatory factor secretion and expression. In a mouse E. coli infection model, administration of MccJ25 effectively improved host defense against clinically source cocktail of multidrug-resistant E. coli strains induced intestinal inflammation and bacteria dissemination. Results of studies on anti-inflammatory mechanisms showed that MccJ25 downregulated nuclear factor kappa B kinase and mitogen-activated protein kinase, thereby reducing the production of toll-like receptor 4, myeloid differentiation factor 88 and decreasing the key proinflammatory cytokines. These findings clarify MccJ25 may be an ideal antibacterial/antiendotoxic drug candidate that has the potential to further guide the development of anti-inflammatory and/or antimicrobial agents in the war against MDR bacterial infection.
Collapse
Affiliation(s)
- Haitao Yu
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Department of Immunology, Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lijun Shang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Guangxin Yang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Ziqi Dai
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
| | - Shiyan Qiao
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Biofeed Additives, China Agricultural University, Beijing, China
- *Correspondence: Shiyan Qiao,
| |
Collapse
|
|
32
|
Mousa WK, Chehadeh F, Husband S. Recent Advances in Understanding the Structure and Function of the Human Microbiome. Front Microbiol 2022; 13:825338. [PMID: 35185849 PMCID: PMC8851206 DOI: 10.3389/fmicb.2022.825338] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/11/2022] [Indexed: 12/11/2022] Open
Abstract
Trillions of microbes live within our bodies in a deep symbiotic relationship. Microbial populations vary across body sites, driven by differences in the environment, immunological factors, and interactions between microbial species. Major advances in genome sequencing enable a better understanding of microbiome composition. However, most of the microbial taxa and species of the human microbiome are still unknown. Without revealing the identity of these microbes as a first step, we cannot appreciate their role in human health and diseases. A shift in the microbial balance, termed dysbiosis, is linked to a broad range of diseases from simple colitis and indigestion to cancer and dementia. The last decade has witnessed an explosion in microbiome research that led to a better understanding of the microbiome structure and function. This understanding leads to potential opportunities to develop next-generation microbiome-based drugs and diagnostic biomarkers. However, our understanding is limited given the highly personalized nature of the microbiome and its complex and multidirectional interactions with the host. In this review, we discuss: (1) our current knowledge of microbiome structure and factors that shape the microbial composition, (2) recent associations between microbiome dysbiosis and diseases, and (3) opportunities of new microbiome-based therapeutics. We analyze common themes, promises, gaps, and challenges of the microbiome research.
Collapse
Affiliation(s)
- Walaa K. Mousa
- College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates
- Department of Biology, Whitman College, Walla Walla, WA, United States
- College of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Fadia Chehadeh
- Department of Biology, Whitman College, Walla Walla, WA, United States
| | - Shannon Husband
- Department of Biology, Whitman College, Walla Walla, WA, United States
| |
Collapse
|
|
33
|
Seco EM, Fernández LÁ. Efficient markerless integration of genes in the chromosome of probiotic E. coli Nissle 1917 by bacterial conjugation. Microb Biotechnol 2021; 15:1374-1391. [PMID: 34755474 PMCID: PMC9049610 DOI: 10.1111/1751-7915.13967] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 10/22/2021] [Accepted: 10/23/2021] [Indexed: 01/30/2023] Open
Abstract
The probiotic strain Escherichia coli Nissle 1917 (EcN) is a common bacterial chassis in synthetic biology developments for therapeutic applications given its long track record of safe administration in humans. Chromosomal integration of the genes of interest (GOIs) in the engineered bacterium offers significant advantages in genetic stability and to control gene dose, but common methodologies relying on the transformation of EcN are inefficient. In this work, we implement in EcN the use of bacterial conjugation in combination with markerless genome engineering to efficiently insert multiple GOIs at different loci of EcN chromosome, leaving no antibiotic resistance genes, vector sequences or scars in the modified bacterium. The resolution of cointegrants that leads to markerless insertion of the GOIs requires expression of I-SceI endonuclease and its efficiency is enhanced by λ Red proteins. We show the potential of this strategy by integrating different genes encoding fluorescent and bioluminescent reporters (i.e. GFP, mKate2, luxCDABE) both individually and sequentially. We also demonstrate its application for gene deletions in EcN (ΔflhDC) and to replace the endogenous regulation of chromosomal locus (i.e. flhDC) by heterologous regulatory elements (e.g. tetR-Ptet) in order to have an ectopic control of gene expression in EcN with an external inducer to alter bacterial behaviour (e.g. flagellar motility). Whole-genome sequencing confirmed the introduction of the designed modifications without off-target alterations in the genome. This straightforward approach accelerates the generation of multiple modifications in EcN chromosome for the generation of living bacterial therapeutics.
Collapse
Affiliation(s)
- Elena M Seco
- Department of Microbial Biotechnology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Darwin 3, Campus UAM Cantoblanco, Madrid, 28049, Spain
| | - Luis Ángel Fernández
- Department of Microbial Biotechnology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Darwin 3, Campus UAM Cantoblanco, Madrid, 28049, Spain
| |
Collapse
|
|
34
|
Sibinelli-Sousa S, de Araújo-Silva AL, Hespanhol JT, Bayer-Santos E. Revisiting the steps of Salmonella gut infection with a focus on antagonistic interbacterial interactions. FEBS J 2021; 289:4192-4211. [PMID: 34546626 DOI: 10.1111/febs.16211] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/12/2021] [Accepted: 09/20/2021] [Indexed: 12/20/2022]
Abstract
A commensal microbial community is established in the mammalian gut during its development, and these organisms protect the host against pathogenic invaders. The hallmark of noninvasive Salmonella gut infection is the induction of inflammation via effector proteins secreted by the type III secretion system, which modulate host responses to create a new niche in which the pathogen can overcome the colonization resistance imposed by the microbiota. Several studies have shown that endogenous microbes are important to control Salmonella infection by competing for resources. However, there is limited information about antimicrobial mechanisms used by commensals and pathogens during these in vivo disputes for niche control. This review aims to revisit the steps that Salmonella needs to overcome during gut colonization-before and after the induction of inflammation-to achieve an effective infection. We focus on a series of reported and hypothetical antagonistic interbacterial interactions in which both contact-independent and contact-dependent mechanisms might define the outcome of the infection.
Collapse
Affiliation(s)
| | | | - Julia Takuno Hespanhol
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil
| | - Ethel Bayer-Santos
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil
| |
Collapse
|
|
35
|
Zeng XY, Li M. Looking into key bacterial proteins involved in gut dysbiosis. World J Methodol 2021; 11:130-143. [PMID: 34322365 PMCID: PMC8299906 DOI: 10.5662/wjm.v11.i4.130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal microbiota plays a pivotal role in health and has been linked to many diseases. With the rapid accumulation of pyrosequencing data of the bacterial composition, the causal-effect relationship between specific dysbiosis features and diseases is now being explored. The aim of this review is to describe the key functional bacterial proteins and antigens in the context of dysbiosis related-diseases. We subjectively classify the key functional proteins into two categories: Primary key proteins and secondary key proteins. The primary key proteins mainly act by themselves and include biofilm inhibitors, toxin degraders, oncogene degraders, adipose metabolism modulators, anti-inflammatory peptides, bacteriocins, host cell regulators, adhesion and invasion molecules, and intestinal barrier regulators. The secondary key proteins mainly act by eliciting host immune responses and include flagellin, outer membrane proteins, and other autoantibody-related antigens. Knowledge of key bacterial proteins is limited compared to the rich microbiome data. Understanding and focusing on these key proteins will pave the way for future mechanistic level cause-effect studies of gut dysbiosis and diseases.
Collapse
Affiliation(s)
- Xin-Yu Zeng
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Ming Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumors, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| |
Collapse
|
|
36
|
Cao L, Do T, Link AJ. Mechanisms of action of ribosomally synthesized and posttranslationally modified peptides (RiPPs). J Ind Microbiol Biotechnol 2021; 48:6121428. [PMID: 33928382 PMCID: PMC8183687 DOI: 10.1093/jimb/kuab005] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/22/2021] [Indexed: 12/19/2022]
Abstract
Natural products remain a critical source of medicines and drug leads. One of the most rapidly growing superclasses of natural products is RiPPs: ribosomally synthesized and posttranslationally modified peptides. RiPPs have rich and diverse bioactivities. This review highlights examples of the molecular mechanisms of action that underly those bioactivities. Particular emphasis is placed on RiPP/target interactions for which there is structural information. This detailed mechanism of action work is critical toward the development of RiPPs as therapeutics and can also be used to prioritize hits in RiPP genome mining studies.
Collapse
Affiliation(s)
- Li Cao
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA
| | - Truc Do
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA
| | - A James Link
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.,Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.,Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| |
Collapse
|
|
37
|
Escherichia coli Strains Producing Selected Bacteriocins Inhibit Porcine Enterotoxigenic Escherichia coli (ETEC) under both In Vitro and In Vivo Conditions. Appl Environ Microbiol 2021; 87:e0312120. [PMID: 33962981 DOI: 10.1128/aem.03121-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) and Shiga toxin-producing E. coli (STEC) strains are the causative agents of severe foodborne diseases in both humans and animals. In this study, porcine pathogenic E. coli strains (n = 277) as well as porcine commensal strains (n = 188) were tested for their susceptibilities to 34 bacteriocin monoproducers to identify the most suitable bacteriocin types inhibiting porcine pathogens. Under in vitro conditions, the set of pathogenic E. coli strains was found to be significantly more susceptible to the majority of tested bacteriocins than commensal E. coli. Based on the production of bacteriocins with specific activity against pathogens, three potentially probiotic commensal E. coli strains of human origin were selected. These strains were found to be able to outcompete ETEC strains expressing F4 or F18 fimbriae in liquid culture and also decreased the severity and duration of diarrhea in piglets during experimental ETEC infection as well as pathogen numbers on the last day of in vivo experimentation. While the extents of the probiotic effect were different for each strain, the cocktail of all three strains showed the most pronounced beneficial effects, suggesting synergy between the tested E. coli strains. IMPORTANCE Increasing levels of antibiotic resistance among bacteria also increase the need for alternatives to conventional antibiotic treatment. Pathogenic Escherichia coli represents a major diarrheic infectious agent of piglets in their postweaning period; however, available measures to control these infections are limited. This study describes three novel E. coli strains producing antimicrobial compounds (bacteriocins) that actively inhibit a majority of toxigenic E. coli strains. The beneficial effect of three potentially probiotic E. coli strains was demonstrated under both in vitro and in vivo conditions. The novel probiotic candidates may be used as prophylaxis during piglets' postweaning period to overcome common infections caused by E. coli.
Collapse
|
|
38
|
Abstract
The human microbiome encodes a second genome that dwarfs the genetic capacity of the host. Microbiota-derived small molecules can directly target human cells and their receptors or indirectly modulate host responses through functional interactions with other microbes in their ecological niche. Their biochemical complexity has profound implications for nutrition, immune system development, disease progression, and drug metabolism, as well as the variation in these processes that exists between individuals. While the species composition of the human microbiome has been deeply explored, detailed mechanistic studies linking specific microbial molecules to host phenotypes are still nascent. In this review, we discuss challenges in decoding these interaction networks, which require interdisciplinary approaches that combine chemical biology, microbiology, immunology, genetics, analytical chemistry, bioinformatics, and synthetic biology. We highlight important classes of microbiota-derived small molecules and notable examples. An understanding of these molecular mechanisms is central to realizing the potential of precision microbiome editing in health, disease, and therapeutic responses.
Collapse
Affiliation(s)
- Emilee E Shine
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA; .,Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA.,Current affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Jason M Crawford
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA; .,Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA.,Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
| |
Collapse
|
|
39
|
Abstract
A balanced gut microbiota contributes to health, but the mechanisms maintaining homeostasis remain elusive. Microbiota assembly during infancy is governed by competition between species and by environmental factors, termed habitat filters, that determine the range of successful traits within the microbial community. These habitat filters include the diet, host-derived resources, and microbiota-derived metabolites, such as short-chain fatty acids. Once the microbiota has matured, competition and habitat filtering prevent engraftment of new microbes, thereby providing protection against opportunistic infections. Competition with endogenous Enterobacterales, habitat filtering by short-chain fatty acids, and a host-derived habitat filter, epithelial hypoxia, also contribute to colonization resistance against Salmonella serovars. However, at a high challenge dose, these frank pathogens can overcome colonization resistance by using their virulence factors to trigger intestinal inflammation. In turn, inflammation increases the luminal availability of host-derived resources, such as oxygen, nitrate, tetrathionate, and lactate, thereby creating a state of abnormal habitat filtering that enables the pathogen to overcome growth inhibition by short-chain fatty acids. Thus, studying the process of ecosystem invasion by Salmonella serovars clarifies that colonization resistance can become weakened by disrupting host-mediated habitat filtering. This insight is relevant for understanding how inflammation triggers dysbiosis linked to noncommunicable diseases, conditions in which endogenous Enterobacterales expand in the fecal microbiota using some of the same growth-limiting resources required by Salmonella serovars for ecosystem invasion. In essence, ecosystem invasion by Salmonella serovars suggests that homeostasis and dysbiosis simply represent states where competition and habitat filtering are normal or abnormal, respectively.
Collapse
|
|
40
|
Telhig S, Ben Said L, Zirah S, Fliss I, Rebuffat S. Bacteriocins to Thwart Bacterial Resistance in Gram Negative Bacteria. Front Microbiol 2020; 11:586433. [PMID: 33240239 PMCID: PMC7680869 DOI: 10.3389/fmicb.2020.586433] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/16/2020] [Indexed: 12/16/2022] Open
Abstract
An overuse of antibiotics both in human and animal health and as growth promoters in farming practices has increased the prevalence of antibiotic resistance in bacteria. Antibiotic resistant and multi-resistant bacteria are now considered a major and increasing threat by national health agencies, making the need for novel strategies to fight bugs and super bugs a first priority. In particular, Gram-negative bacteria are responsible for a high proportion of nosocomial infections attributable for a large part to Enterobacteriaceae, such as pathogenic Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. To cope with their highly competitive environments, bacteria have evolved various adaptive strategies, among which the production of narrow spectrum antimicrobial peptides called bacteriocins and specifically microcins in Gram-negative bacteria. They are produced as precursor peptides that further undergo proteolytic cleavage and in many cases more or less complex posttranslational modifications, which contribute to improve their stability and efficiency. Many have a high stability in the gastrointestinal tract where they can target a single pathogen whilst only slightly perturbing the gut microbiota. Several microcins and antibiotics can bind to similar bacterial receptors and use similar pathways to cross the double-membrane of Gram-negative bacteria and reach their intracellular targets, which they also can share. Consequently, bacteria may use common mechanisms of resistance against microcins and antibiotics. This review describes both unmodified and modified microcins [lasso peptides, siderophore peptides, nucleotide peptides, linear azole(in)e-containing peptides], highlighting their potential as weapons to thwart bacterial resistance in Gram-negative pathogens and discusses the possibility of cross-resistance and co-resistance occurrence between antibiotics and microcins in Gram-negative bacteria.
Collapse
Affiliation(s)
- Soufiane Telhig
- Institute of Nutrition and Functional Foods, Université Laval, Québec, QC, Canada
- Laboratory Molecules of Communication and Adaptation of Microorganisms, Muséum National d’Histoire Naturelle, Centre National de la Recherche Scientifique, Paris, France
| | - Laila Ben Said
- Institute of Nutrition and Functional Foods, Université Laval, Québec, QC, Canada
| | - Séverine Zirah
- Laboratory Molecules of Communication and Adaptation of Microorganisms, Muséum National d’Histoire Naturelle, Centre National de la Recherche Scientifique, Paris, France
| | - Ismail Fliss
- Institute of Nutrition and Functional Foods, Université Laval, Québec, QC, Canada
| | - Sylvie Rebuffat
- Laboratory Molecules of Communication and Adaptation of Microorganisms, Muséum National d’Histoire Naturelle, Centre National de la Recherche Scientifique, Paris, France
| |
Collapse
|
|
41
|
Jeckelmann JM, Erni B. The mannose phosphotransferase system (Man-PTS) - Mannose transporter and receptor for bacteriocins and bacteriophages. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183412. [PMID: 32710850 DOI: 10.1016/j.bbamem.2020.183412] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/08/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023]
Abstract
Mannose transporters constitute a superfamily (Man-PTS) of the Phosphoenolpyruvate Carbohydrate Phosphotransferase System (PTS). The membrane complexes are homotrimers of protomers consisting of two subunits, IIC and IID. The two subunits without recognizable sequence similarity assume the same fold, and in the protomer are structurally related by a two fold pseudosymmetry axis parallel to membrane-plane (Liu et al. (2019) Cell Research 29 680). Two reentrant loops and two transmembrane helices of each subunit together form the N-terminal transport domain. Two three-helix bundles, one of each subunit, form the scaffold domain. The protomer is stabilized by a helix swap between these bundles. The two C-terminal helices of IIC mediate the interprotomer contacts. PTS occur in bacteria and archaea but not in eukaryotes. Man-PTS are abundant in Gram-positive bacteria living on carbohydrate rich mucosal surfaces. A subgroup of IICIID complexes serve as receptors for class IIa bacteriocins and as channel for the penetration of bacteriophage lambda DNA across the inner membrane. Some Man-PTS are associated with host-pathogen and -symbiont processes.
Collapse
Affiliation(s)
- Jean-Marc Jeckelmann
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
| | - Bernhard Erni
- Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
| |
Collapse
|
|
42
|
Wu D, Li X, Yu Y, Gong B, Zhou X. Heparin stimulates biofilm formation of Escherichia coli strain Nissle 1917. Biotechnol Lett 2020; 43:235-246. [PMID: 33011901 DOI: 10.1007/s10529-020-03019-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 09/29/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Escherichia coli strain Nissle 1917 (EcN), a gut probiotic competing with pathogenic bacteria, has been used to attenuate various intestinal dysfunctions. Heparin is a sulfated glycosaminoglycan enriched in the human and animal intestinal mucosa, which has a close connection with bacterial biofilm formation. However, the characteristics of heparin affecting bacterial biofilm formation remain obscure. In this study, we investigated the influence of heparin and its derivatives on EcN biofilm formation. RESULTS Here, we found that heparin stimulated EcN biofilm formation in a dose-dependent manner. With the addition of native heparin, the EcN biofilm formation increased 6.9- to 10.8-fold than that without heparin, and was 1.4-, 3.1-, 3.0-, and 3.8-fold higher than that of N-desulfated heparin (N-DS), 2-O-desulfated heparin (2-O-DS), 6-O-desulfated heparin (6-O-DS), and N-/2-O-/6-O-desulfated heparin (N-/2-O-/6-O-DS), respectively. Depolymerization of heparin produced chain-shortened heparin fragments with decreased molecular weight. The depolymerized heparins did not stimulate EcN biofilm formation. The OD570 value of EcN biofilm with the addition of chain-shortened heparin fragments was 8.7-fold lower than that of the native heparin. Furthermore, the biofilm formation of Salmonella enterica serovar Typhimurium was also investigated with the addition of heparin derivatives, and the results were consistent with that of EcN biofilm formation. CONCLUSIONS We conclude that heparin stimulated EcN biofilm formation. Both the sulfation and chain-length of heparin contributed to the enhancement of EcN biofilm formation. This study increases the understanding of how heparin affects biofilm formation, indicating the potential role of heparin in promoting intestinal colonization of probiotics that antagonize pathogen infections.
Collapse
Affiliation(s)
- Dandan Wu
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Xiaomei Li
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Yanying Yu
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Bingxue Gong
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Xianxuan Zhou
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, 230009, China.
| |
Collapse
|
|
43
|
Ohno M, Hasegawa M, Hayashi A, Caballero-Flores G, Alteri CJ, Lawley TD, Kamada N, Núñez G, Inohara N. Lipopolysaccharide O structure of adherent and invasive Escherichia coli regulates intestinal inflammation via complement C3. PLoS Pathog 2020; 16:e1008928. [PMID: 33027280 PMCID: PMC7571687 DOI: 10.1371/journal.ppat.1008928] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/19/2020] [Accepted: 08/25/2020] [Indexed: 12/28/2022] Open
Abstract
Gut dysbiosis associated with intestinal inflammation is characterized by the blooming of particular bacteria such as adherent-invasive E. coli (AIEC). However, the precise mechanisms by which AIEC impact on colitis remain largely unknown. Here we show that antibiotic-induced dysbiosis worsened chemically-induced colitis in IL-22-deficient mice, but not in wild-type mice. The increase in intestinal inflammation was associated with the expansion of E. coli strains with genetic and functional features of AIEC. These E. coli isolates exhibited high ability to out compete related bacteria via colicins and resistance to the host complement system in vitro. Mutation of wzy, the lipopolysaccharide O polymerase gene, rendered AIEC more sensitive to the complement system and more susceptible to engulfment and killing by phagocytes while retaining its ability to outcompete related bacteria in vitro. The wzy AIEC mutant showed impaired fitness to colonize the intestine under colitic conditions, but protected mice from chemically-induced colitis. Importantly, the ability of the wzy mutant to protect from colitis was blocked by depletion of complement C3 which was associated with impaired intestinal eradication of AIEC in colitic mice. These studies link surface lipopolysaccharide O-antigen structure to the regulation of colitic activity in commensal AIEC via interactions with the complement system.
Collapse
Affiliation(s)
- Masashi Ohno
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Mizuho Hasegawa
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Atsushi Hayashi
- Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- Miyarisan Pharmaceutical Co., Ltd., Central Research Institute, Saitama, Japan
| | - Gustavo Caballero-Flores
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Christopher J. Alteri
- Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, Michigan, United States of America
| | - Trevor D. Lawley
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Nobuhiko Kamada
- Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Gabriel Núñez
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Naohiro Inohara
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| |
Collapse
|
|
44
|
Massip C, Oswald E. Siderophore-Microcins in Escherichia coli: Determinants of Digestive Colonization, the First Step Toward Virulence. Front Cell Infect Microbiol 2020; 10:381. [PMID: 32974212 PMCID: PMC7472721 DOI: 10.3389/fcimb.2020.00381] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/22/2020] [Indexed: 12/17/2022] Open
Abstract
Siderophore-microcins are antimicrobial peptides produced by enterobacteria, especially Escherichia coli and Klebsiella pneumoniae strains. The antibiotic peptide is post-translationally modified by the linkage of a siderophore moiety. Therefore, it can enter and kill phylogenetically related bacteria by a “Trojan Horse” stratagem, by mimicking the iron–siderophore complexes. Consequently, these antimicrobial peptides are key determinants of bacterial competition within the intestinal niche, which is the reservoir for pathogenic E. coli. The most frequent extraintestinal infections caused by E. coli are urinary tract infections. Uropathogenic E. coli (UPEC) can produce many virulence factors, including siderophore-microcins. Siderophore-microcins are chromosomally encoded by small genomic islands that exhibit conserved organization. In UPEC, the siderophore-microcin gene clusters and biosynthetic pathways differ from the “archetypal” models described in fecal strains. The gene cluster is shorter. Thus, active siderophore-microcin production requires proteins from two other genomic islands that also code for virulence factors. This functional and modular synergy confers a strong selective advantage for the domination of the colonic niche, which is the first step toward infection. This optimization of genetic resources might favor the selection of additional virulence factors, which are essential in the subsequent steps of pathogenesis in E. coli infection.
Collapse
Affiliation(s)
- Clémence Massip
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.,Service de Bactériologie-Hygiène, Hôpital Purpan, CHU de Toulouse, Toulouse, France
| | - Eric Oswald
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.,Service de Bactériologie-Hygiène, Hôpital Purpan, CHU de Toulouse, Toulouse, France
| |
Collapse
|
|
45
|
Mazurek-Popczyk J, Pisarska J, Bok E, Baldy-Chudzik K. Antibacterial Activity of Bacteriocinogenic Commensal Escherichia coli against Zoonotic Strains Resistant and Sensitive to Antibiotics. Antibiotics (Basel) 2020; 9:E411. [PMID: 32679778 PMCID: PMC7400030 DOI: 10.3390/antibiotics9070411] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/05/2020] [Accepted: 07/13/2020] [Indexed: 12/23/2022] Open
Abstract
Antibiotic resistance concerns various areas with high consumption of antibiotics, including husbandry. Resistant strains are transmitted to humans from livestock and agricultural products via the food chain and may pose a health risk. The commensal microbiota protects against the invasion of environmental strains by secretion of bacteriocins, among other mechanisms. The present study aims to characterize the bactericidal potential of bacteriocinogenic Escherichia coli from healthy humans against multidrug-resistant and antibiotic-sensitive strains from pigs and cattle. Bacteriocin production was tested by the double-layer plate method, and bacteriocin genes were identified by the PCR method. At least one bacteriocinogenic E. coli was detected in the fecal samples of 55% of tested individuals, adults and children. Among all isolates (n = 210), 37.1% were bacteriocinogenic and contained genes of colicin (Col) Ib, ColE1, microcin (Mcc) H47, ColIa, ColM, MccV, ColK, ColB, and single ColE2 and ColE7. Twenty-five E. coli carrying various sets of bacteriocin genes were further characterized and tested for their activity against zoonotic strains (n = 60). Strains with ColE7 (88%), ColE1-ColIa-ColK-MccH47 (85%), MccH47-MccV (85%), ColE1-ColIa-ColM (82%), ColE1 (75%), ColM (67%), and ColK (65%) were most active against zoonotic strains. Statistically significant differences in activity toward antibiotic-resistant strains were shown by commensal E. coli carrying MccV, ColK-MccV, and ColIb-ColK. The study demonstrates that bacteriocinogenic commensal E. coli exerts antagonistic activity against zoonotic strains and may constitute a defense line against multidrug-resistant strains.
Collapse
Affiliation(s)
- Justyna Mazurek-Popczyk
- Department of Microbiology and Molecular Biology, Collegium Medicum, University of Zielona Góra, 65-417 Zielona Góra, Poland; (J.P.); (E.B.); (K.B.-C.)
| | | | | | | |
Collapse
|
|
46
|
Metabolomics Study on Pathogenic and Non-pathogenic E. coli with Closely Related Genomes with a Focus on Yersiniabactin and Its Known and Novel Derivatives. Metabolites 2020; 10:metabo10060221. [PMID: 32481767 PMCID: PMC7344775 DOI: 10.3390/metabo10060221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/22/2020] [Accepted: 05/24/2020] [Indexed: 11/18/2022] Open
Abstract
The Escherichia coli (E. coli) strains Nissle 1917 (EcN), 83972 and CFT073 are closely related but differ in their phenotypes and pathogenicity. The aim of this study was to compare the metabolome of these strains based on metabolomic data analysis of bacterial samples using liquid chromatography-high resolution mass spectrometry (LC-HRMS). The strains were cultivated in minimum essential medium at 37 °C for 6 h. The sterilized culture supernatant was analyzed, followed by data processing to create feature lists, and statistical analysis to identify discriminating features in the metabolomes of the three strains. Metabolites were identified using the exact masses, isotope patterns, and fragmentation spectra. The results showed that the metabolome of EcN differs significantly from the metabolomes of E. coli 83972 and CFT073. Based on the analysis, yersiniabactin (Ybt), its metal complexes, and its known structural derivatives escherichelin and ulbactin B were identified as discriminating features; the latter has not been described for E. coli before. Additionally, novel Ytb derivatives were found and tentatively identified by LC-MS/HRMS. All these metabolites were determined in significantly higher levels in the metabolome of EcN compared to E. coli 83972, which may explain a large part of the observed differences of the metabolomes.
Collapse
|
|
47
|
Simons A, Alhanout K, Duval RE. Bacteriocins, Antimicrobial Peptides from Bacterial Origin: Overview of Their Biology and Their Impact against Multidrug-Resistant Bacteria. Microorganisms 2020; 8:E639. [PMID: 32349409 PMCID: PMC7285073 DOI: 10.3390/microorganisms8050639] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/16/2020] [Accepted: 04/22/2020] [Indexed: 12/18/2022] Open
Abstract
Currently, the emergence and ongoing dissemination of antimicrobial resistance among bacteria are critical health and economic issue, leading to increased rates of morbidity and mortality related to bacterial infections. Research and development for new antimicrobial agents is currently needed to overcome this problem. Among the different approaches studied, bacteriocins seem to be a promising possibility. These molecules are peptides naturally synthesized by ribosomes, produced by both Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB), which will allow these bacteriocin producers to survive in highly competitive polymicrobial environment. Bacteriocins exhibit antimicrobial activity with variable spectrum depending on the peptide, which may target several bacteria. Already used in some areas such as agro-food, bacteriocins may be considered as interesting candidates for further development as antimicrobial agents used in health contexts, particularly considering the issue of antimicrobial resistance. The aim of this review is to present an updated global report on the biology of bacteriocins produced by GPB and GNB, as well as their antibacterial activity against relevant bacterial pathogens, and especially against multidrug-resistant bacteria.
Collapse
Affiliation(s)
- Alexis Simons
- Université de Lorraine, CNRS, L2CM, F-54000 Nancy, France
- Institut Micalis, équipe Bactéries Pathogènes et Santé, Faculté de Pharmacie, Université Paris-Saclay—INRAE—AgroParisTech, 92296 Châtenay-Malabry, France
| | - Kamel Alhanout
- Université de Lorraine, CNRS, L2CM, F-54000 Nancy, France
| | - Raphaël E. Duval
- Université de Lorraine, CNRS, L2CM, F-54000 Nancy, France
- ABC Platform, Faculté de Pharmacie, F-54505 Vandœuvre-lès-Nancy, France
| |
Collapse
|
|
48
|
Tsolis RM, Bäumler AJ. Gastrointestinal host-pathogen interaction in the age of microbiome research. Curr Opin Microbiol 2020; 53:78-89. [PMID: 32344325 DOI: 10.1016/j.mib.2020.03.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 02/06/2023]
Abstract
The microbiota is linked to human health by governing susceptibility to infection. However, the interplay between enteric pathogens, the host, and its microbiota is complex, encompassing host cell manipulation by virulence factors, immune responses, and a diverse gut ecosystem. The host represents a foundation species that uses its immune system as a habitat filter to shape the gut microbiota. In turn, the gut microbiota protects against ecosystem invasion by opportunistic pathogens through priority effects that are based on niche modification or niche preemption. Frank pathogens can overcome these priority effects by using their virulence factors to manipulate host-derived habitat filters, thereby constructing new nutrient-niches in the intestinal lumen that support ecosystem invasion. The emerging picture identifies pathogens as ecosystem engineers and suggests that virulence factors are useful tools for identifying host-derived habitat filters that balance the microbiota.
Collapse
Affiliation(s)
- Renée M Tsolis
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Andreas J Bäumler
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA.
| |
Collapse
|
|
49
|
Palmer JD, Mortzfeld BM, Piattelli E, Silby MW, McCormick BA, Bucci V. Microcin H47: A Class IIb Microcin with Potent Activity Against Multidrug Resistant Enterobacteriaceae. ACS Infect Dis 2020; 6:672-679. [PMID: 32096972 DOI: 10.1021/acsinfecdis.9b00302] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Microcin H47 (MccH47) is an antimicrobial peptide produced by some strains of Escherichia coli that has demonstrated inhibitory activity against enteric pathogens in vivo and has been heterologously overexpressed in proof-of-concept engineered probiotic applications. While most studies clearly demonstrate inhibitory activity against E. coli isolates, there are conflicting results on the qualitative capacity for MccH47 to inhibit strains of Salmonella. Here, we rectify these inconsistencies via the overexpression and purification of a form of MccH47, termed MccH47-monoglycosylated enterobactin (MccH47-MGE). We then use purified MccH47 to estimate minimum inhibitory concentrations (MICs) against a number of medically relevant Enterobacteriaceae, including Salmonella and numerous multidrug resistant (MDR) strains. While previous reports suggested that the spectrum of activity for MccH47 is quite narrow and restricted to activity against E. coli, our data demonstrate that MccH47 has broad and potent activity within the Enterobacteriaceae family, suggesting it as a candidate for further development toward treating MDR enteric infections.
Collapse
Affiliation(s)
- Jacob D. Palmer
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, N. Dartmouth, Massachusetts 02747-2300, United States
| | - Benedikt M. Mortzfeld
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, N. Dartmouth, Massachusetts 02747-2300, United States
- Department of Biology, University of Massachusetts Dartmouth, 285 Old Westport Road, N. Dartmouth, Massachusetts 02747-2300, United States
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, United States
| | - Emma Piattelli
- Department of Biology, University of Massachusetts Dartmouth, 285 Old Westport Road, N. Dartmouth, Massachusetts 02747-2300, United States
| | - Mark W. Silby
- Department of Biology, University of Massachusetts Dartmouth, 285 Old Westport Road, N. Dartmouth, Massachusetts 02747-2300, United States
| | - Beth A. McCormick
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, United States
- Center for Microbiome Research, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, United States
| | - Vanni Bucci
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, N. Dartmouth, Massachusetts 02747-2300, United States
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, United States
- Center for Microbiome Research, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, United States
| |
Collapse
|
|
50
|
Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat Commun 2020; 11:1738. [PMID: 32269218 PMCID: PMC7142098 DOI: 10.1038/s41467-020-15508-1] [Citation(s) in RCA: 230] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 03/13/2020] [Indexed: 12/29/2022] Open
Abstract
A complex interplay of metabolic and immunological mechanisms underlies many diseases that represent a substantial unmet medical need. There is an increasing appreciation of the role microbes play in human health and disease, and evidence is accumulating that a new class of live biotherapeutics comprised of engineered microbes could address specific mechanisms of disease. Using the tools of synthetic biology, nonpathogenic bacteria can be designed to sense and respond to environmental signals in order to consume harmful compounds and deliver therapeutic effectors. In this perspective, we describe considerations for the design and development of engineered live biotherapeutics to achieve regulatory and patient acceptance. The role microbes play in human health and the ability of synthetic biology to engineer microbial properties opens up new ways of treating disease. In this perspective, the authors describe the design and development of these living therapeutics.
Collapse
|