• antimicrobial therapy
• biofilms
• molecular docking
• molecular dynamics
• quercetin
• quorum sensing

• (E)‐1‐methyl‐4‐(2‐nitrovinyl)benzene
• Serratia marcescens
• biofilms
• quorum sensing
• virulence factors

• Antimicrobial resistance
• gram-negative pathogens
• quorum sensing
• traditional foods

• Pseudomonas aeruginosa/drug effects
• Furans/pharmacology
• Furans/chemistry
• Arctium/chemistry
• Lignans/pharmacology
• Lignans/chemistry
• Anti-Bacterial Agents/pharmacology
• Anti-Bacterial Agents/chemistry
• Animals
• Mice
• Virulence/drug effects
• Plant Roots/chemistry
• Biofilms/drug effects
• Microbial Sensitivity Tests
• Quorum Sensing/drug effects
• Pseudomonas Infections/drug therapy
• Pseudomonas Infections/microbiology
• Plant Extracts/pharmacology
• Plant Extracts/chemistry
• Cell Membrane/drug effects

• National Natural Science Foundation of China

• Serratia marcescens
• case report
• infection route
• peritoneal dialysis
• peritonitis
• treatment

• Humans
• Serratia marcescens/isolation & purification
• Male
• Peritonitis/microbiology
• Peritonitis/drug therapy
• Adult
• Serratia Infections/microbiology
• Anti-Bacterial Agents/therapeutic use
• Anti-Bacterial Agents/administration & dosage
• Peritoneal Dialysis/adverse effects
• Treatment Outcome
• Device Removal
• Levofloxacin/therapeutic use
• Ceftazidime/therapeutic use
• Ceftazidime/administration & dosage
• Cefazolin/therapeutic use

• State Administration of Traditional Chinese Medicine of the People's Republic of China
• Traditional Chinese Medicine Bureau of Guangdong Province

• Pseudomonas aeruginosa
• Serratia marcescens
• bacterial virulence inhibition
• glyceryl trinitrate
• quorum sensing

• Antibiotic resistance
• K. pneumoniae
• Metformin
• N-acetylcysteine
• Secnidazole
• Virulence inhibitors

• Animals
• Mice
• Virulence
• Acetylcysteine/pharmacology
• Klebsiella pneumoniae/genetics
• Metformin
• Virulence Factors/genetics

• Port Said University

Diabetes is a chronic disease that is considered one of the most stubborn global health problems that continues to defy the efforts of scientists and physicians. The prevalence of diabetes in the global population continues to grow to alarming levels year after year, causing an increase in the incidence of diabetes complications and health care costs all over the world. One major complication of diabetes is the high susceptibility to infections especially in the lower limbs due to the immunocompromised state of diabetic patients, which is considered a definitive factor in all cases. Diabetic foot infections continue to be one of the most common infections in diabetic patients that are associated with a high risk of serious complications such as bone infection, limb amputations, and life-threatening systemic infections. In this review, we discussed the circumstances associated with the high risk of infection in diabetic patients as well as some of the most commonly isolated pathogens from diabetic foot infections and the related virulence behavior. In addition, we shed light on the different treatment strategies that aim at eradicating the infection.

• Diabetic foot infection
• Chronic ulcer
• Bacterial biofilm
• Multidrug resistance
• Methicillin resistant Staphylococcus aureus
• Vancomycin resistance

• Pseudomonas aeruginosa
• anti-virulence agents
• healthcare
• metformin
• quorum sensing
• vildagliptin

• Anti-virulence
• Bacterial resistance
• Doxazosin
• Gram-negative bacteria
• Quorum sensing
• α-adrenoreceptor blocker

• IFPIP:1623-166-1443 King Abdulaziz University

• anti-virulence agents
• biofilm eradication
• biofilm formation
• catheter-associated urinary tract infections
• recurrent urinary tract infections

• Pseudomonas aeruginosa
• antimicrobial resistance
• bacterial virulence
• drug repurposing
• linagliptin
• quorum sensing

• Salmonella enterica
• anti-biofilm
• antimicrobial resistance
• prazosin
• virulence

• Gram-negative
• Quorum sensing
• anti-biofilm
• antimicrobial resistance
• atenolol
• virulence

• Mice
• Animals
• Atenolol/pharmacology
• Atenolol/metabolism
• Virulence Factors/genetics
• Quorum Sensing
• Biofilms
• Gram-Negative Bacteria
• Pseudomonas aeruginosa
• Serratia marcescens/metabolism
• Anti-Bacterial Agents/pharmacology
• Anti-Bacterial Agents/metabolism
• Proteus mirabilis/metabolism
• Bacterial Proteins/metabolism

• E. coli
• Salmonella Typhimurium
• atenolol
• biofilm
• quorum sensing
• virulence

• IFPRC-002-249-2020 King Abdulaziz University

Bacterial infections are considered one of the main challenges to global health. Bacterial virulence is controlled by interplayed systems to regulate bacterial invasion and infection in host tissues. Quorum sensing (QS) plays a crucial role in regulating virulence factor production, thus could be considered as the bacterial communication system in the bacterial population. The current study aimed to assess the anti-QS and anti-virulence activities of α-adrenoreceptor prazosin against three virulent Gram-negative bacteria. It was demonstrated that prazosin significantly downregulates the expression of QS-encoding genes and shows considered ability to compete on QS proteins in tested strains. Prazosin can significantly diminish biofilm formation and production of virulent enzymes and mitigate the virulence factors of tested strains. However, more testing is required alongside pharmacological and toxicological studies to assure the potential clinical use of prazosin as an adjuvant anti-QS and anti-virulence agent.

Quorum sensing (QS) controls the production of several bacterial virulence factors. There is accumulative evidence to support that targeting QS can ensure a significant diminishing of bacterial virulence. Lessening bacterial virulence has been approved as an efficient strategy to overcome the development of antimicrobial resistance. The current study aimed to assess the anti-QS and anti-virulence activities of α-adrenoreceptor prazosin against three virulent Gram-negative bacteria Pseudomonades aeruginosa, Proteus mirabilis, and Serratia marcescens. The evaluation of anti-QS was carried out on a series of in vitro experiments, while the anti-virulence activities of prazosin were tested in an in vivo animal model. The prazosin anti-QS activity was assessed on the production of QS-controlled Chromobacterium violaceum pigment violacein and the expression of QS-encoding genes in P. aeruginosa. In vitro tests were performed to evaluate the prazosin effects on biofilm formation and production of extracellular enzymes by P. aeruginosa, P. mirabilis, and S. marcescens. A protective assay was conducted to evaluate the in vivo anti-virulence activity of prazosin against P. aeruginosa, P. mirabilis, and S. marcescens. Moreover, precise in silico molecular docking was performed to test the prazosin affinity to different QS receptors. The results revealed that prazosin significantly decreased the production of violacein and the virulent enzymes, protease and hemolysins, in the tested strains. Prazosin significantly diminished biofilm formation in vitro and bacterial virulence in vivo. The prazosin anti-QS activity was proven by its downregulation of QS-encoding genes and its obvious binding affinity to QS receptors. In conclusion, prazosin could be considered an efficient anti-virulence agent to be used as an adjuvant to antibiotics, however, it requires further pharmacological evaluations prior to clinical application.

Quorum sensing plays a necessary role in the production of virulence factors and the formation of biofilm on Pseudomonas aeruginosa. Thus, the development of inhibition of quorum sensing is one of the most promising methods to control bacterial infection and antibiotic resistance. In this work, nine novel AHL analogs were designed, synthesized, and evaluated as potential quorum sensing inhibitors. The results depicted that structural modifications have significant effects on quorum sensing inhibition activity of AHL molecules. Without inhibiting the growth of P. aeruginosa, 2-(4-bromophenyl)-N-(2-oxotetrapyridinefuran-3-yl) butanamide (compound no.10) showed the excellent performance in inhibiting biofilm formation and virulence factor production among all the compounds through robustly suppressing the expression of QS related genes. In a molecular docking study, compound no.10 exhibited a higher affinity toward LasR than other AHL analogs. In addition, compound no.10 also exhibits the best inhibition effect on virulence production in the Caenorhabditis elegans infection model.

• National Natural Science Foundation of China

The development of bacterial resistance is an insistent global health care issue, especially in light of the dwindled supply of new antimicrobial agents. This mandates the development of new innovative approaches to overcome the resistance development obstacle. Mitigation of bacterial virulence is an interesting approach that offers multiple advantages. Employing safe chemicals or drugs to mitigate bacterial virulence is an additive advantage. In the current study, the in vitro antivirulence activities of citrate were evaluated. Significantly, sodium citrate inhibited bacterial biofilm formation at sub-MIC concentrations. Furthermore, sodium citrate decreased the production of virulence factors protease and pyocyanin and diminished bacterial motility. Quorum sensing (QS) is the communicative system that bacterial cells utilize to communicate with each other and regulate the virulence of the host cells. In the present study, citrate in silico blocked the Pseudomonas QS receptors and downregulated the expression of QS-encoding genes. In conclusion, sodium citrate showed a significant ability to diminish bacterial virulence in vitro and interfered with QS; it could serve as a safe adjuvant to traditional antibiotic treatment for aggressive resistant bacterial infections such as Pseudomonas aeruginosa infections.

• antivirulence
• bacterial resistance
• gliptins
• industrial development
• quorum sensing

Antimicrobial resistance is among the world’s most urgent public health problems. Diminishing of the virulence of bacteria is a promising approach to decrease the development of bacterial resistance. Quorum sensing (QS) systems orchestrate the bacterial virulence in inducer–receptors manner. Bacteria can spy on the cells of the host by sensing adrenergic hormones and other neurotransmitters, and in turn, these neurotransmitters can induce bacterial pathogenesis. In this direction, α-adrenergic blockers were proposed as an anti-virulence agents through inhibiting the bacterial espionage. The current study aimed to explore the α-blockers’ anti-QS activities. Within comprehensive in silico investigation, the binding affinities of seven α-adrenoreceptor blockers were evaluated towards structurally different QS receptors. From the best docked α-blockers into QS receptors, terazosin was nominated to be subjected for further in vivo and in vitro anti-QS and anti-virulence activities against Chromobacterium violaceum and Pseudomonas aeruginosa. Terazosin showed a significant ability to diminish the QS-controlled pigment production in C. violaceum. Moreover, Terazosin decreased the P. aeruginosa biofilm formation and down-regulated its QS-encoding genes. Terazosin protected mice from the P. aeruginosa pathogenesis. In conclusion, α-adrenergic blockers are proposed as promising anti-virulence agents as they hinder QS receptors and inhibit bacterial espionage.

Since the synthesis of prontosil the first prodrug shares their chemical moiety, sulfonamides exhibit diverse modes of actions to serve as antimicrobials, diuretics, antidiabetics, and other clinical applications. This inspiring chemical nucleus has promoted several research groups to investigate the synthesis of new members exploring new clinical applications. In this study, a novel series of 5(4H)-oxazolone-based-sulfonamides (OBS) 9a–k were synthesized, and their antibacterial and antifungal activities were evaluated against a wide range of Gram-positive and -negative bacteria and fungi. Most of the tested compounds exhibited promising antibacterial activity against both Gram-positive and -negative bacteria particularly OBS 9b and 9f. Meanwhile, compound 9h showed the most potent antifungal activity. Moreover, the OBS 9a, 9b, and 9f that inhibited the bacterial growth at the lowest concentrations were subjected to further evaluation for their anti-virulence activities against Pseudomonas aeruginosa and Staphylococcus aureus. Interestingly, the three tested compounds reduced the biofilm formation and diminished the production of virulence factors in both P. aeruginosa and S. aureus. Bacteria use a signaling system, quorum sensing (QS), to regulate their virulence. In this context, in silico study has been conducted to assess the ability of OBS to compete with the QS receptors. The tested OBS showed marked ability to bind and hinder QS receptors, indicating that anti-virulence activities of OBS could be due to blocking QS, the system that controls the bacterial virulence. Furthermore, anticancer activity has been further performed for such derivatives. The OBS compounds showed variable anti-tumor activities, specifically 9a, 9b, 9f and 9k, against different cancer lines. Conclusively, the OBS compounds can serve as antimicrobials, anti-virulence and anti-tumor agents.

Salmonella enterica is a common cause of many enteric infections worldwide and is successfully engineered to deliver heterologous antigens to be used as vaccines. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) RNA-guided Cas9 endonuclease is a promising genome editing tool. In the current study, a CRISPR-Cas9 system was used to target S.enterica sdiA that encodes signal molecule receptor SdiA and responds to the quorum sensing (QS) signaling compounds N-acylhomoserine lactones (AHLs). For this purpose, sdiA was targeted in both S.enterica wild type (WT) and the ΔssaV mutant strain, where SsaV has been reported to be an essential component of SPI2-T3SS. The impact of sdiA mutation on S. enterica virulence was evaluated at both early invasion and later intracellular replication in both the presence and absence of AHL. Additionally, the influence of sdiA mutation on the pathogenesis S. enterica WT and mutants was investigated in vivo, using mice infection model. Finally, the minimum inhibitory concentrations (MICs) of various antibiotics against S. enterica strains were determined. Present findings show that mutation in sdiA significantly affects S.enterica biofilm formation, cell adhesion and invasion. However, sdiA mutation did not affect bacterial intracellular survival. Moreover, in vivo bacterial pathogenesis was markedly lowered in S.enterica ΔsdiA in comparison with the wild-type strain. Significantly, double-mutant sdiA and ssaV attenuated the S. enterica virulence and in vivo pathogenesis. Moreover, mutations in selected genes increased Salmonella susceptibility to tested antibiotics, as revealed by determining the MICs and MBICs of these antibiotics. Altogether, current results clearly highlight the importance of the CRISPR-Cas9 system as a bacterial genome editing tool and the valuable role of SdiA in S.enterica virulence. The present findings extend the understanding of virulence regulation and host pathogenesis of Salmonellaenterica.

• CRISPR-Cas9
• Salmonella enterica
• pathogenesis
• sdiA
• ssaV
• virulence

Diabetes is one of the four major non-communicable diseases, and appointed by the world health organization as the seventh leading cause of death worldwide. The scientists have turned over every rock in the corners of medical sciences in order to come up with better understanding and hence more effective treatments of diabetes. The continuous research on the subject has elucidated the role of immune disorders and inflammation as definitive factors in the trajectory of diabetes, assuring that blood glucose adjustments would result in a relief in the systemic stress leading to minimizing inflammation. On a parallel basis, microbial infections usually take advantage of immunity disorders and propagate creating a pro-inflammatory environment, all of which can be reversed by antimicrobial treatment. Standing at the crossroads between diabetes, immunity and infection, we aim in this review at projecting the interplay between immunity and diabetes, shedding the light on the overlapping playgrounds for the activity of some antimicrobial and anti-diabetic agents. Furthermore, we focused on the anti-diabetic drugs that can confer antimicrobial or anti-virulence activities.

• Diabetes
• Immune disorders
• Anti-diabetics
• Antimicrobials
• Anti-virulence

• Pseudomonas aeruginosa
• allopurinol
• quorum sensing
• virulence inhibition

• Serratia marcescens
• anti-quorum sensing agents
• anti-virulence agents
• pathogenesis
• quorum sensing
• secnidazole
• virulence factors

The bacterial resistance development due to the incessant administration of antibiotics has led to difficulty in their treatment. Natural adjuvant compounds can be co-administered to hinder the pathogenesis of resistant bacteria. Sotolon is the prevailing aromatic compound that gives fenugreek its typical smell. In the current work, the anti-virulence activities of sotolon on Pseudomonas aeruginosa have been evaluated. P. aeruginosa has been treated with sotolon at sub-minimum inhibitory concentration (MIC), and production of biofilm and other virulence factors were assessed. Moreover, the anti-quorum sensing (QS) activity of sotolon was in-silico evaluated by evaluating the affinity of sotolon to bind to QS receptors, and the expression of QS genes was measured in the presence of sotolon sub-MIC. Furthermore, the sotolon in-vivo capability to protect mice against P. aeruginosa was assessed. Significantly, sotolon decreased the production of bacterial biofilm and virulence factors, the expression of QS genes, and protected mice from P. aeruginosa. Conclusively, the plant natural substance sotolon attenuated the pathogenicity of P. aeruginosa, locating it as a plausible potential therapeutic agent for the treatment of its infections. Sotolon can be used in the treatment of bacterial infections as an alternative or adjuvant to antibiotics to combat their high resistance to antibiotics.

• Pseudomonas aeruginosa
• antibiotic resistance
• natural furanone
• sotolon
• virulence inhibition

Serratia marcescens is an opportunistic nosocomial pathogen and causes wound and burn infections. It shows high resistance to antibiotics and its pathogenicity is mediated by an arsenal of virulence factors. Another therapeutic option to such infections is targeting quorum sensing (QS), which controls the expression of different S. marcescens virulence factors. Prevention of QS can deprive S. marcescens from its bacterial virulence without applying stress on the bacterial growth and facilitates the eradication of the bacteria by immunity. The objective of the current study is to explore the antimicrobial and antivirulence activities of xylitol against S. marcescens. Xylitol could inhibit the growth of S. marcescens. Sub-inhibitory concentrations of xylitol could inhibit biofilm formation, reduce prodigiosin production, and completely block protease activity. Moreover, xylitol decreased swimming motility, swarming motility and increased the sensitivity to hydrogen peroxide. The expression of rsmA, pigP, flhC, flhD fimA, fimC, shlA bsmB, and rssB genes that regulate virulence factor production was significantly downregulated by xylitol. In silico study showed that xylitol could bind with the SmaR receptor by hydrophobic interaction and hydrogen bonding, and interfere with the binding of the natural ligand with SmaR receptor. An in vivo mice survival test confirmed the ability of xylitol to protect mice against the virulence of S. marcescens. In conclusion, xylitol is a growth and virulence inhibitor in S. marcescens and can be employed for the treatment of S. marcescens wound and burn infections.

• Serratia marcescens
• quorum sensing
• virulence
• xylitol