Editorial Open Access
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastrointest Pathophysiol. Jun 15, 2011; 2(3): 35-41
Published online Jun 15, 2011. doi: 10.4291/wjgp.v2.i3.35
Mechanisms of Helicobacter pylori antibiotic resistance: An updated appraisal
Vincenzo De Francesco, Floriana Giorgio, Rosa Rosania, Enzo Ierardi, Section of Gastroenterology, Department of Medical Sciences, University of Foggia, Foggia 71100, Italy
Angelo Zullo, Cesare Hassan, Gastroenterology and Digestive Endoscopy, ‘Nuovo Regina Margherita’ Hospital, Rome 00153, Italy
Author contributions: Ierardi E, De Francesco V, Zullo A and Hassan C designed the study, revised the manuscript and approved the final version; Rosania R and Giorgio F collected the data.
Correspondence to: Enzo Ierardi, Professor, Gastroenterology Section, Department of Medical Sciences, University of Foggia, AOU Ospedali Riuniti, Viale Pinto, Foggia 71100, Italy. enzo.ierardi@fastwenet.it
Telephone: +39-0881736204 Fax: +39-0881733848
Received: February 18, 2011
Revised: May 29, 2011
Accepted: June 5, 2011
Published online: June 15, 2011

Abstract

Helicobacter pylori (H. pylori) antibiotic resistance is the main factor affecting the efficacy of the current eradicating therapies. The aim of this editorial is to report on the recent information about the mechanisms accounting for the resistance to the different antibiotics currently utilized in H. pylori eradicating treatments. Different mechanisms of resistance to clarithromycin, metronidazole, quinolones, amoxicillin and tetracycline are accurately detailed (point mutations, redox intracellular potential, pump efflux systems, membrane permeability) on the basis of the most recent data available from the literature. The next hope for the future is that by improving the knowledge of resistance mechanisms, the elaboration of rational and efficacious associations for the treatment of the infection will be possible. Another auspicious progress might be the possibility of a cheap, feasible and reliable laboratory test to predict the outcome of a therapeutic scheme.

Key Words: Helicobacter pylori, Clarithromycin, Metronidazole, Levofloxacin, Amoxicillin, Tetracycline, Resistance, Antibiotic, Point mutation



INTRODUCTION

The discovery of Helicobacter pylori (H. pylori) infection and its role in different diseases from chronic gastritis to gastric cancer has radically changed the management of patients with this condition. Unfortunately, the goal of achieving a cure in all treated patients at the first therapeutic approach, as generally occurs for common infective diseases, has not been achieved for H. pylori. Indeed, it has been immediately evident that only a few antibiotics are active against such a bacterium in the acidic environment of the stomach.

The initial susceptibility of H. pylori to both clarithromycin and imidazoles, key drugs for triple first-line therapies, has progressively been undergoing a marked reduction and the eradication rate following therapy regimens including these antibiotics is decreasing[1]. Similarly, the low H. pylori resistance rate towards quinolones, mainly used for second-line therapy, observed in the past has increased during the last decade, whilst both amoxicillin and tetracycline resistance rates seem to have remained low[2]. Alternative molecules, such as furazolidone, bismuth salts and rifabutin are not available worldwide and they are not free of significant side-effects. All these observations highlight the crucial role of antibiotic resistance in the management of H. pylori infection[3,4]. Therefore, the knowledge of resistance mechanisms may contribute to elaborate more rational antibiotic combinations with the aim of improving treatment success.

We reviewed the mechanisms of H. pylori antibiotic resistance towards the drugs mainly used, including clarithromycin, metronidazole, levofloxacin, amoxicillin and tetracycline.

CLARITHROMYCIN

Clarithromycin remains the currently available most powerful antibiotic against H. pylori with minimal inhibitor concentrations (MICs) being the lowest as compared to the other molecules. Indeed, MIC values as low as 0.016-0.5 mg/L are generally reported, antibiotic resistance being recognized with MIC values ≥ 1.0 mg/l (range: 2-256 mg/L)[5,6]. The bacteriostatic activity of clarithromycin depends on its capacity to inhibit the protein synthesis by binding to the 50S bacterial ribosomal subunit. Extensive studies by PCR-based tools have demonstrated that point mutations in the peptidyltransferase region encoded in domain V of 23S rRNA are responsible for the bacterial resistance to macrolides[7]. These mutations are able to inhibit the binding between clarithromycin and the ribosomal subunit dedicated to the specific antibiotic related protein synthesis[7,8]. The more frequent mutations associated with clarithromycin resistance are the transition adenine to cytosine in 2143 and 2142 positions of rRNA, whilst the substitution of adenine with cytosine in 2142 position is less frequent. These mutational events are responsible for more than 90% of clarithromycin resistance in developed countries[9]. In detail, the mutation at position 2143 seems to be associated with different resistance levels rather than an on/off behavior, with MIC values widely ranging from 0.016 to 256 mg/L. Conversely, the mutations at position 2142 are associated with more restricted MIC values, close to 64 mg/L[10,11]. Of note, we found that the presence of the A2143G point mutation, rather than the A2142G or A2142C mutation, markedly reduces H. pylori eradication rate[12]. These data should suggest that a mutational event detected in vitro does not precisely predict in vivo results[13].

Several other point mutations have been identified such as A2115G, G2141A, T2117C and T2182C, T2289C, G224A, C2245T, C2611A. Besides the low frequency, the clinical relevance of the A2115G, G2141A, T2117C T2289C, G224A, C2245T mutation is still not proven, their role not being consistently reported[14,15], whilst the T2182C and C2611A have been associated with low resistance levels[16,17].

Another relevant mechanism for macrolide resistance is ascribed to the efflux pump system. At least 5 conserved families of drug efflux mechanisms are associated to bacterial species, including Small Multidrug Resistance, Multidrug and Toxic Compounds Extrusion proteins, the Major Facilitator Superfamily, the ATP-Binding Cassette Superfamilies and the Resistance-Nodulation Cell Division[18]. The Resistance-Nodulation-cell Division (RND family) is responsible for macrolide intrinsic resistance in several Gram negative bacteria and it has been recently proposed also for H. pylori. In detail, it has been observed that 4 RND gene clusters (HP0605-HP0607, HP0971-HP0969, HP1327-HP1329, HP1489-HP1487) in the efflux pump system play a role in promoting multidrug H. pylori resistance[19]. These systems of excretion can be inhibited by the administration of specific Efflux Pump Inhibitors (EPI), such as Phe-Arg-β-naphthylamide (PAβN). Indeed, EPI-administration is associated with a relevant intracellular entrapment of antibiotic and a significant decrease of MIC values. In detail, a dose-dependent reduction of MIC values in 15 rRNA point mutate resistant strains has been demonstrated by using PAβN. Increased intracellular antibiotic concentrations able to compensate the reduced drug affinity for the mutate ribosomal site have been postulated as a possible mechanism. This effect is constantly associated with the HP0605-HP0607 cluster gene. Interestingly, a different effect of EPI administration on MIC values is observed between susceptible and rRNA mutate strains. A possible explanation is that, in susceptible strains, clarithromycin binds preferentially to the ribosomal subunits rather than the efflux pumps. Consequently, the excretive activity of efflux pumps becomes irrelevant, the effect of PAβN on MIC value modifications vanishing. On the contrary, in the rRNa mutate strains, clarithromycin is preferentially excreted by the efflux pumps because of its low affinity with the mutate ribosomal site, with the more relevant impact of efflux pumps inhibition by PAβN on MIC values[20]. Based on these findings, it is reasonable to hypothesize that PAβN (or PAβN-like molecules) administration could improve the eradicating efficacy of the clarithromycin-based therapies by increasing its intracellular entrapment.

The possible interaction between the RND efflux pump system and proton pump inhibitors (PPIs) due to structural analogies is also of clinical interest. Besides the deep gastric acid inhibition, PPIs may inhibit the activity of bacterial efflux pumps, similar to EPI drugs. Interestingly, MIC values of clarithromycin, as well as metronidazole, amoxicillin and furazolidone, are decreased 4-fold and 3-fold in H. pylori multi-resistant strains by using rabeprazole and pantoprazole respectively, whilst no significant effect is observed with omeprazole, esomeprazole and lansoprazole[21]. These differences should be considered when choosing the PPI in eradication regimens.

METRONIDAZOLE

Mechanisms of metronidazole resistance have been extensively investigated and new information has been recently obtained[22]. In H. pylori strains, MIC values of 0.5-2 mg/L are reported, antibiotic resistance being recognized with MIC values ≥ 8 mg/L (range: 16-128 mg/L)[5,23]. Bactericide activity of metronidazole depends on the reduction of its nitro-groups in anionic radicals, nitroso-derivates and hydroxylamines which are able to damage the DNA-helicoidal structure. These reactions of reduction are strongly dependent on the intracellular redox potential of components of electron transport chain which needs to be effectively negative. In detail, electrons are produced by the Pyruvate Oxido Reductase complex (POR) and are passed to either ferredoxin or flavodoxin which, in turn, reduce other molecules as metronidazole[24]. This process is particularly active in anaerobe species which are highly susceptible to metronidazole. The acquisition of antibiotic resistance depends on the reduction or abolition of activity of the electron carriers. On the contrary, the high intracellular redox potential of aerobe species prevents the metronidazole reduction-activation and is responsible for the intrinsic resistance of these bacteria[25].

A further action mechanism of metronidazole against anaerobe bacteria in aerobe conditions consists in the production of oxygen-free radicals. In this case, the oxygen acts as the last acceptor of electrons from reduced metronidazole, leading to the regeneration of the parent inactive antibiotic (futile cycle) and the production of oxygen-free radicals which are toxic for DNA structure[26]. In resistant strains, such a bactericide effect is neutralised by a catalase-superoxide dismutase system with final water production. This enzymatic system increases its activity in the presence of metronidazole[25,27]. The intracellular redox potential/oxygen tension also plays a relevant role in the resistance of microaerophilic species, such as H. pylori, in which catalase/superoxide dismutase is not present. Of note, the pre-exposure of H. pylori resistant strains to anaerobic conditions is associated with a loss of resistance and restoration of metronidazole susceptibility[28]. In this event, a NADH oxidase acts as an ‘oxygen scavenger’ assuring low redox potential/oxygen tension and maintaining the antibiotic in the active form. An inactive mutate NADH oxidase and intracellular higher redox potential/oxygen tension have been found in H. pylori resistant strains[29].

Different mutations involving the rdxA gene which encodes for an oxygen insensitive NADPH nitro-reductase have been identified in metronidazole resistant strains. These mutations are recognized as the main mechanism conferring metronidazole resistance in H. pylori[30]. In the susceptible strains, NADPH nitro-reductase reduces several compounds, including metronidazole, by 2 electrons transfer and generating toxic nitro-derivates for DNA. For example, the activation of NADPH in E. coli, which is usually resistant to metronidazole, generates susceptible strains. Besides these mutations, other and more complex genetic events (insertions and deletions of transposons, missense and frameshift mutations) could be simultaneously present in the rdxA gene. These events complicate metronidazole resistance assessment by bio-molecular tools[31-33].

More recently, the inactivation of other reductases, encoded by genes as frxA (for NADPH flavin oxidoreductase) and frxB (for ferredoxin-like enzymes), has been investigated. There is evidence that these point mutations are able to increase bacterial resistance exclusively in the presence of rdxA gene mutations[23,34-35]. Indeed, the rare cases of metronidazole resistant strains in the absence of rdxA mutations have been attributed to mutations involving genes outside the rdxA which can, in turn, down-modulate its expression[36].

A role for a complex efflux system responsible for metronidazole in H. pylori strains has been recently reported. In detail, the presence of Outer membrane Efflux Proteins (OEP) in H. pylori which interact with several intracellular translocases and regulate secretion of different antibiotics has been found. Of note, the inactivation of 2 OEPs (HP0605 and HP0971) in a double-knockout mutant strain significantly increased susceptibility towards metronidazole, supporting a significant role for this efflux pump system in metronidazole resistance[19].

LEVOFLOXACIN

The use of levofloxacin for H. pylori eradication is increasing worldwide because of its role in ‘rescue therapy’ regimens following the failure of clarithromycin-based treatments. MIC values of 0.25-0.50 mg/L are generally reported, antibiotic resistance being recognized with MIC values ≥ 1 mg/L (range: 4-32 mg/L)[37,38]. Fluoroquinolones exert a dose-dependent bactericide effect by binding the sub-unit A of DNA gyrase (topoisomerase II), an essential enzyme for the maintenance of DNA helicoidal structure. In susceptible strains, levofloxacin stops DNA and, at high doses, even RNA synthesis. Surprisingly, when the dose is further increased, quinolones become bacteriostatic agents.

Point mutations in Quinolones Resistance-Determining Region (QRDR) of gyrA prevent binding between the antibiotic and the enzyme, conferring antibiotic bacterial resistance[39]. Different studies found the involvement of the following H. pylori loci: (1) position 91 (Asp91Gly, Asn, Ala, or Tyr); (2) position 87 (Asn87Lys); and (3) position 88 (Ala88Val)[39-41]. Mutations in both 91 and 87 position have been observed in the 100% of levofloxacin resistant isolates and a new mutation consisting in the substitution of Asn with Tyr in position 87 has been additionally identified[37]. Rare mutations involve the position 86 (Asp86Asn) which, in turn, is usually associated with the mutations at 87 and 91 positions[37], lowering its role on MIC values. Similarly, the constant association between the gyrB with the gyrA 87-91 mutations most likely minimize the role of the gyrB mutations in quinolone resistance[42]. Indeed, gyrA and gyrB gene mutations involvement in levofloxacin resistance has been observed in 83.8% and 4.4% respectively[43].

Other factors involved in levofloxacin resistance are an amino acidic polymorphism in the codon 87 of gyrA, consisting in the presence of different asparagyne-threonine residues. In detail, the complete sequencing genome of 2 strains, i.e. the 26695 and the J99, allowed identifying the presence of threonine in the J99 strain and asparagyne residues in the 26695 strain associated with a higher antibiotic susceptibility. Interestingly, the presence of threonine residue at 87 codon is also conserved in other. Helicobacter types thus indicating the possibility of a “philogenic” evolution of Helicobacter species[37].

AMOXICILLIN

Amoxicillin is a β-lactam antibiotic included in all current therapeutic regimens for H. pylori eradication[4]. MIC values ranging from 0.06 to 0.25 mg/L are generally reported in susceptible strains, antibiotic resistance being recognized with MIC values ≥ 1 (range: 1-8 mg/L)[5,44]. Amoxicillin acts by interfering with the peptidoglycan synthesis, especially by blocking transporters named penicillin binding proteins (PBP)[5]. This drug has been the first antibiotic used in H. pylori therapy because of a presumed absence of resistance. Nevertheless, the evidence of stable amoxicillin resistant strains, with a MIC of 8 mg/L, has been reported[45]. Moreover, an instable amoxicillin resistance has been described in H. pylori isolates, the resistance being peculiarly lost upon freezing the culture at -80°C. Such an unusual condition has been defined as ‘amoxicillin tolerance’ rather than resistance[46].

Different mechanisms have been invoked in the stable amoxicillin resistance. The Penicillin Binding Proteins (PBPs) are enzymes involved in the synthesis of the peptidoglycan layer of the bacterial wall by a glycosyl transferase-acyl transpeptidase activity. This enzymatic activity is located in the C-terminal region, in 3 distinct motifs (SKN368-371, SNN433-435, KTG555-557) of PBPs. The first motif occupies a central position in the catalytic cleft whereas second and third motifs are dislocated on the outside. PBP1, PBP2, PBP3 are reported as high molecular PBPs whilst PBP4 is reported as low molecular protein. The β-lactam binding to PBPs motifs leads a bactericide effect by synthetic interruption of the peptidoglycan layer, as well as an osmotic bacterial shock. Production of β-lactamase, i. e. the main mechanism of penicillin resistance in other bacteria, has been consistently found to be inactive in H. pylori[47-49].

Several investigations indicate that multiple point mutations in pbp1 gene are the major mechanism of amoxicillin resistance, leading to a loss of affinity between amoxicillin and PBP-transpeptidase[44,50]. It has been observed that the Ser414 to Arg substitution, adjacent to the SKN motif in PBP1, is responsible for amoxicillin resistance with a significantly increased MIC (> 0.5-1 mg/L)[49]. Another study reported the substitution of Asn562 aminoacid with a Tyr residue in proximity to KTG motif of PBP1. Such a point mutation is able to confer high resistance to all strains in vitro and is considered the main mutation conferring resistance. Other substitutions (Ala369 to Thr, Val374 to Leu, Leu423 to Phe, Thr593 to Ala) not constantly associated with Asn562-Tyr seem to play an additive role in increasing MIC values of the resistant strains similarly to point mutations in PBP2, in PBP3 and PBP4[48,51]. Interestingly, H. pylori resistant strains obtained by transformation in vitro of susceptible naive strains, exhibit MIC values 5-10 fold lower than naïve resistant strains[49], suggesting that several and concomitant mechanisms are probably involved in conferring the high levels observed in natural antibiotic resistance.

The outer bacterial membrane constitutes a first barrier for accounting for an intrinsic and not specific resistance. Indeed, the variable fluidity of lipopolysac caridic layer is able to limit the diffusion of several lipophilic compounds. Recent findings indicate that “porin” narrow channels, encoded in H. pylori by hopB and hopC genes, regulate the penetration of small solutes. Point mutations in hopB and a deletion in hopC gene are associated with reduced amoxicillin accumulation in all naïve mutant and transformed strains, with a consequent increase of MIC values (250 mg/L for hopB gene and 125 mg/L for hopC gene)[44]. When point mutations either in hopB or in hopC are associated with mutations in PBP1 gene (triple mutants), a further increase of MIC values (400 mg/L) is observed. These findings could suggest that channels and PBP1 mutations are factors able to support the resistance[44,52]. It has been reported that several encoding “porin” genes could be over-regulated (omp25 porin gene) or down-regulated (omp32 porin gene) by antibiotic exposure leading to alterations in the membrane permeability. Comparable alterations of permeability are likely associated to variable expression of genes involved in import/export/binding of metals[53].

Finally, the efflux of molecules is a frequently reported event in bacteria as a protective process from the toxic effect of environmental compound accumulation. Nevertheless, it seems unlikely that amoxicillin resistance is sustained by these mechanisms because amoxicillin shows a very low hydrophobicity which is an indispensable requirement for substrates of multidrug efflux pumps[54,55].

TETRACYCLINE

Tetracycline is a fundamental antibiotic in quadruple regimens for H. pylori eradication. MIC values 0.25-2 mg/L[56] are generally reported, antibiotic resistance being recognized with MIC values ≥ 4[5]. Bacterial resistance towards such a drug, although still rare, appears to be increasing. Tetracycline acts as a bacteriostatic against either Gram positive or Gram negative species by inhibiting codon-anticodon link at level of 30S ribosomal subunit and blocking the attachment of aminoacyl-tRNA to the acceptor site. Resistant strains show wide range of MIC values (2-256 mg/L). Recent studies have identified 2-6 possible sites for antibiotic-ribosome interaction at high affinity, whilst several biochemical investigations reported multiple, likely hundreds, sites at low affinity[57,58]. Simultaneous triple point mutations from the 965 to 967 position in loop of helix 31 - i.e. the crucial part of primary acceptor site (site P) is recognized as the major mechanism of tetracycline resistance. The main point mutation is a substitution of an AGA with a TTC triplet[59,60] and it reduces the affinity of 24%-52%[61]. Levels of resistance are proportional to the number of changes in the AGA 965-967. Single and double point mutations are associated with low and intermediate MIC values whilst high resistance levels are observed in the presence of a triple mutation from AGA 956 to 957. In detail, among the possible mutations in AGA triplet, the substitution involving the Guanine in the central position is associated with higher MIC values, suggesting that purine base plays a more consistent role in the configuration of the primary site. Purine-rich sequences in the loop of helix 31 are more frequently observed in susceptible strains, whilst pyrimidine-rich loops are in the resistant strains. It is possible that pyrimidine-rich sequences in helix 31 are not compatible with tetracycline conformation, leading to a decreasing affinity[60]. Another study found a deletion of G942 in all resistant strains. This guanine base is located in Tet-4 site, in proximity of primary P site. Since the affinity of tetracycline for Tet-4 site is significantly lower than those for primary P site, Tet-4 may be considered an accessory site for the antibiotic activity in susceptible strains. Therefore, the loss of affinity due to a deletion G492 in such a site may exert a marginal role in the increasing bacterial resistance[62] (Table 1).

Table 1 Minimal inhibitory concentrations of the different antibiotics (left side) and main mechanisms of resistance induction for each antibiotic (right side).
AntibioticsMIC in susceptible strainsMIC in resistant strainsMechanisms of resistance
Clarithromycin0.016-0.50 mg/L≥ 1 mg/L (2-256 mg/L)Point mutations in rRNA
Efflux pumps system (RND family)
Metronidazole0.5-2 mg/L≥ 8 mg/L (16-128 mg/L)Mutate NADPH reductase
Mutate NADH oxidase
Other efflux pumps
Levoxacin0.25-0.50 mg/L≥ 1 mg/L (4-32 mg/L)Point mutations in QRDR of gyrA gene
Polymorphism in 87 codon of gyrA
Amoxicillin0.06-0.25 mg/L≥ 1.0mg/L (1-8 mg/L)Point mutations in pbp genes
Point mutations in hpB and hpC genes
Point mutations in omp25 and omp32 porin genes
Tetracycline0.25- 2 mg/L≥ 4 mg/L (2-256 mg/L)Point mutations in primary binding Tet-P site
Point mutations in Tet-4 secondary inding site
Alterations by oxidoreductase

Serial exposures of susceptible strains on antibiotic are unable to confer resistance whereas the exposition to mutate resistant DNA leads easily transformation. These data indicate a horizontal spread of mutate genome rather than a vertical or parental transformation[62]. Of note, resistant transformants from susceptible strains exhibit intermediate MIC values between parental susceptible strains (4-8 mg/dL) and natural resistant strains (> 32 mg/dL)[61,63]. Such a finding would indicate that factors other than point mutations in 30S ribosomal subunit may work in concert for the tetracycline resistance development. Indeed, resistant strains without point mutations have been observed[61].

Another mechanism of tetracycline resistance is attributed to ribosomal protection by the soluble protein Tet (O). Such a protein removes the antibiotic from ribosome preventing the arrest of protein synthesis[64]. In addition a chemical modification of tetracycline by an oxidoreductase NADP-dependent may interfere in the binding between antibiotic and the ribosomal site[58].

Decreased membrane permeability and a reduced intracellular accumulation of tetracycline were observed in tetracycline resistant strains, which are also cross-resistant to amoxicillin. This finding suggests an identical profile of outer protein for both antibiotics. Finally, the possible role of a specific tetracycline efflux pumps system affecting intracellular drug concentrations has been investigated with discordant results. Indeed, pre-exposure of resistant strains to a de-energizing agent such as cyanide m-chlorophenylhydrazone (CCCP) leads to variable reductions of MIC values[21,58]. However, the role of either specific pumps unaffected by CCCP or a variable expression of not specific multidrug efflux pumps, such as the MexAB-OprM system, cannot be excluded and should be further investigated[62,63].

CONCLUSION

The amount of data we have reported in this editorial reveals that the knowledge about H. pylori antibiotic resistance is a topic with a rapidly and constantly increasing interest. Future perspectives hope for new information aimed at elaborating novel and rational antibiotic associations very effective for H. pylori infection cure in clinical practice. Another “fascinating challenge” could be a feasible, cheap and not time consuming laboratory investigation able to predict the treatment outcome and address the best therapeutic choice case by case.

Footnotes

Peer reviewers: Cinzia Domeneghini, Professor, Veterinary Sci. Technol. for Food Safety, University of Milan, via Celoria n.10, Milan I-20133, Italy; Elvan Özbek, Professor, Histology and Embryology, Ataturk University, Faculty of Medicine, Histoloji ve Embriyoloji Anabilim Dali, Ataturk Universitesi, Tip Fakultesi, Morfoloji Binasi, Erzurum TR-25240, Turkey

S- Editor Zhang HN L- Editor Roemmele A E- Editor Zhang L

References
1.  Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59:1143-1153.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 652]  [Cited by in F6Publishing: 694]  [Article Influence: 49.6]  [Reference Citation Analysis (0)]
2.  Boyanova L, Mitov I. Geographic map and evolution of primary Helicobacter pylori resistance to antibacterial agents. Expert Rev Anti Infect Ther. 2010;8:59-70.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Vakil N, Megraud F. Eradication therapy for Helicobacter pylori. Gastroenterology. 2007;133:985-1001.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Malfertheiner P, Megraud F, O’Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56:772-781.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clin Microbiol Rev. 2007;20:280-322.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 476]  [Cited by in F6Publishing: 459]  [Article Influence: 27.0]  [Reference Citation Analysis (0)]
6.  Elviss NC, Owen RJ, Breathnach A, Palmer C, Shetty N. Helicobacter pylori antibiotic-resistance patterns and risk factors in adult dyspeptic patients from ethnically diverse populations in central and south London during 2000. J Med Microbiol. 2005;54:567-574.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 22]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
7.  Versalovic J, Shortridge D, Kibler K, Griffy MV, Beyer J, Flamm RK, Tanaka SK, Graham DY, Go MF. Mutations in 23S rRNA are associated with clarithromycin resistance in Helicobacter pylori. Antimicrob Agents Chemother. 1996;40:477-480.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  van Doorn LJ, Debets-Ossenkopp YJ, Marais A, Sanna R, Mégraud F, Kusters JG, Quint WG. Rapid detection, by PCR and reverse hybridization, of mutations in the Helicobacter pylori 23S rRNA gene, associated with macrolide resistance. Antimicrob Agents Chemother. 1999;43:1779-1782.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Mégraud F. H pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut. 2004;53:1374-1384.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 607]  [Cited by in F6Publishing: 648]  [Article Influence: 32.4]  [Reference Citation Analysis (1)]
10.  García-Arata MI, Baquero F, de Rafael L, Martín de Argila C, Gisbert JP, Bermejo F, Boixeda D, Cantón R. Mutations in 23S rRNA in Helicobacter pylori conferring resistance to erythromycin do not always confer resistance to clarithromycin. Antimicrob Agents Chemother. 1999;43:374-376.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Versalovic J, Osato MS, Spakovsky K, Dore MP, Reddy R, Stone GG, Shortridge D, Flamm RK, Tanaka SK, Graham DY. Point mutations in the 23S rRNA gene of Helicobacter pylori associated with different levels of clarithromycin resistance. J Antimicrob Chemother. 1997;40:283-286.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 143]  [Cited by in F6Publishing: 145]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
12.  De Francesco V, Margiotta M, Zullo A, Hassan C, Troiani L, Burattini O, Stella F, Di Leo A, Russo F, Marangi S. Clarithromycin-resistant genotypes and eradication of Helicobacter pylori. Ann Intern Med. 2006;144:94-100.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  De Francesco V, Zullo A, Ierardi E, Vaira D. Minimal inhibitory concentration (MIC) values and different point mutations in the 23S rRNA gene for clarithromycin resistance in Helicobacter pylori. Dig Liver Dis. 2009;41:610-611.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 22]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
14.  Fontana C, Favaro M, Minelli S, Criscuolo AA, Pietroiusti A, Galante A, Favalli C. New site of modification of 23S rRNA associated with clarithromycin resistance of Helicobacter pylori clinical isolates. Antimicrob Agents Chemother. 2002;46:3765-3769.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 65]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
15.  Hultén K, Gibreel A, Sköld O, Engstrand L. Macrolide resistance in Helicobacter pylori: mechanism and stability in strains from clarithromycin-treated patients. Antimicrob Agents Chemother. 1997;41:2550-2553.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Rimbara E, Noguchi N, Kawai T, Sasatsu M. Novel mutation in 23S rRNA that confers low-level resistance to clarithromycin in Helicobacter pylori. Antimicrob Agents Chemother. 2008;52:3465-3466.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 28]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
17.  Kim JM, Kim JS, Kim N, Kim YJ, Kim IY, Chee YJ, Lee CH, Jung HC. Gene mutations of 23S rRNA associated with clarithromycin resistance in Helicobacter pylori strains isolated from Korean patients. J Microbiol Biotechnol. 2008;18:1584-1589.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Paulsen IT. Multidrug efflux pumps and resistance: regulation and evolution. Curr Opin Microbiol. 2003;6:446-451.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 145]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
19.  van Amsterdam K, Bart A, van der Ende A. A Helicobacter pylori TolC efflux pump confers resistance to metronidazole. Antimicrob Agents Chemother. 2005;49:1477-1482.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 77]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
20.  Hirata K, Suzuki H, Nishizawa T, Tsugawa H, Muraoka H, Saito Y, Matsuzaki J, Hibi T. Contribution of efflux pumps to clarithromycin resistance in Helicobacter pylori. J Gastroenterol Hepatol. 2010;25 Suppl 1:S75-S79.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 84]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
21.  Zhang Z, Liu ZQ, Zheng PY, Tang FA, Yang PC. Influence of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori. World J Gastroenterol. 2010;16:1279-1284.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 60]  [Cited by in F6Publishing: 50]  [Article Influence: 3.6]  [Reference Citation Analysis (2)]
22.  Jenks PJ, Edwards DI. Metronidazole resistance in Helicobacter pylori. Int J Antimicrob Agents. 2002;19:1-7.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 73]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
23.  Matteo MJ, Pérez CV, Domingo MR, Olmos M, Sanchez C, Catalano M. DNA sequence analysis of rdxA and frxA from paired metronidazole-sensitive and -resistant Helicobacter pylori isolates obtained from patients with heteroresistance. Int J Antimicrob Agents. 2006;27:152-158.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 19]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
24.  Smith MA, Edwards DI. Redox potential and oxygen concentration as factors in the susceptibility of Helicobacter pylori to nitroheterocyclic drugs. J Antimicrob Chemother. 1995;35:751-764.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 51]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
25.  Edwards DI. Nitroimidazole drugs--action and resistance mechanisms. II. Mechanisms of resistance. J Antimicrob Chemother. 1993;31:201-210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 113]  [Cited by in F6Publishing: 116]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
26.  Docampo R, Moreno SN. Free radical metabolism of antiparasitic agents. Fed Proc. 1986;45:2471-2476.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Wassmann C, Hellberg A, Tannich E, Bruchhaus I. Metronidazole resistance in the protozoan parasite Entamoeba histolytica is associated with increased expression of iron-containing superoxide dismutase and peroxiredoxin and decreased expression of ferredoxin 1 and flavin reductase. J Biol Chem. 1999;274:26051-26056.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 180]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
28.  Smith MA, Edwards DI. The influence of microaerophilia and anaerobiosis on metronidazole uptake in Helicobacter pylori. J Antimicrob Chemother. 1995;36:453-461.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 25]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
29.  Smith MA, Edwards DI. Oxygen scavenging, NADH oxidase and metronidazole resistance in Helicobacter pylori. J Antimicrob Chemother. 1997;39:347-353.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 39]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
30.  Goodwin A, Kersulyte D, Sisson G, Veldhuyzen van Zanten SJ, Berg DE, Hoffman PS. Metronidazole resistance in Helicobacter pylori is due to null mutations in a gene (rdxA) that encodes an oxygen-insensitive NADPH nitroreductase. Mol Microbiol. 1998;28:383-393.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 271]  [Cited by in F6Publishing: 281]  [Article Influence: 10.8]  [Reference Citation Analysis (0)]
31.  Tankovic J, Lamarque D, Delchier JC, Soussy CJ, Labigne A, Jenks PJ. Frequent association between alteration of the rdxA gene and metronidazole resistance in French and North African isolates of Helicobacter pylori. Antimicrob Agents Chemother. 2000;44:608-613.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 53]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
32.  Debets-Ossenkopp YJ, Pot RG, van Westerloo DJ, Goodwin A, Vandenbroucke-Grauls CM, Berg DE, Hoffman PS, Kusters JG. Insertion of mini-IS605 and deletion of adjacent sequences in the nitroreductase (rdxA) gene cause metronidazole resistance in Helicobacter pylori NCTC11637. Antimicrob Agents Chemother. 1999;43:2657-2662.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Kwon DH, Peña JA, Osato MS, Fox JG, Graham DY, Versalovic J. Frameshift mutations in rdxA and metronidazole resistance in North American Helicobacter pylori isolates. J Antimicrob Chemother. 2000;46:793-796.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 27]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
34.  Kwon DH, El-Zaatari FA, Kato M, Osato MS, Reddy R, Yamaoka Y, Graham DY. Analysis of rdxA and involvement of additional genes encoding NAD(P)H flavin oxidoreductase (FrxA) and ferredoxin-like protein (FdxB) in metronidazole resistance of Helicobacter pylori. Antimicrob Agents Chemother. 2000;44:2133-2142.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 98]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
35.  Yang YJ, Wu JJ, Sheu BS, Kao AW, Huang AH. The rdxA gene plays a more major role than frxA gene mutation in high-level metronidazole resistance of Helicobacter pylori in Taiwan. Helicobacter. 2004;9:400-407.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 24]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
36.  Moore JM, Salama NR. Mutational analysis of metronidazole resistance in Helicobacter pylori. Antimicrob Agents Chemother. 2005;49:1236-1237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 21]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
37.  Cattoir V, Nectoux J, Lascols C, Deforges L, Delchier JC, Megraud F, Soussy CJ, Cambau E. Update on fluoroquinolone resistance in Helicobacter pylori: new mutations leading to resistance and first description of a gyrA polymorphism associated with hypersusceptibility. Int J Antimicrob Agents. 2007;29:389-396.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 80]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
38.  Glupczynski Y, Mégraud F, Lopez-Brea M, Andersen LP. European multicentre survey of in vitro antimicrobial resistance in Helicobacter pylori. Eur J Clin Microbiol Infect Dis. 2001;20:820-823.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 184]  [Cited by in F6Publishing: 191]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
39.  Glocker E, Kist M. Rapid detection of point mutations in the gyrA gene of Helicobacter pylori conferring resistance to ciprofloxacin by a fluorescence resonance energy transfer-based real-time PCR approach. J Clin Microbiol. 2004;42:2241-2246.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 43]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
40.  Fujimura S, Kato S, Iinuma K, Watanabe A. In vitro activity of fluoroquinolone and the gyrA gene mutation in Helicobacter pylori strains isolated from children. J Med Microbiol. 2004;53:1019-1022.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 41]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
41.  Bogaerts P, Berhin C, Nizet H, Glupczynski Y. Prevalence and mechanisms of resistance to fluoroquinolones in Helicobacter pylori strains from patients living in Belgium. Helicobacter. 2006;11:441-445.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 57]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
42.  Tankovic J, Lascols C, Sculo Q, Petit JC, Soussy CJ. Single and double mutations in gyrA but not in gyrB are associated with low- and high-level fluoroquinolone resistance in Helicobacter pylori. Antimicrob Agents Chemother. 2003;47:3942-3944.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 102]  [Cited by in F6Publishing: 111]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
43.  Miyachi H, Miki I, Aoyama N, Shirasaka D, Matsumoto Y, Toyoda M, Mitani T, Morita Y, Tamura T, Kinoshita S. Primary levofloxacin resistance and gyrA/B mutations among Helicobacter pylori in Japan. Helicobacter. 2006;11:243-249.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 108]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
44.  Co EM, Schiller NL. Resistance mechanisms in an in vitro-selected amoxicillin-resistant strain of Helicobacter pylori. Antimicrob Agents Chemother. 2006;50:4174-4176.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 27]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
45.  van Zwet AA, Vandenbroucke-Grauls CM, Thijs JC, van der Wouden EJ, Gerrits MM, Kusters JG. Stable amoxicillin resistance in Helicobacter pylori. Lancet. 1998;352:1595.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 64]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
46.  Dore MP, Osato MS, Realdi G, Mura I, Graham DY, Sepulveda AR. Amoxycillin tolerance in Helicobacter pylori. J Antimicrob Chemother. 1999;43:47-54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 81]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
47.  Dore MP, Graham DY, Sepulveda AR. Different penicillin-binding protein profiles in amoxicillin-resistant Helicobacter pylori. Helicobacter. 1999;4:154-161.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 48]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
48.  Rimbara E, Noguchi N, Kawai T, Sasatsu M. Correlation between substitutions in penicillin-binding protein 1 and amoxicillin resistance in Helicobacter pylori. Microbiol Immunol. 2007;51:939-944.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Gerrits MM, Godoy AP, Kuipers EJ, Ribeiro ML, Stoof J, Mendonça S, van Vliet AH, Pedrazzoli J, Kusters JG. Multiple mutations in or adjacent to the conserved penicillin-binding protein motifs of the penicillin-binding protein 1A confer amoxicillin resistance to Helicobacter pylori. Helicobacter. 2006;11:181-187.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 45]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
50.  Okamoto T, Yoshiyama H, Nakazawa T, Park ID, Chang MW, Yanai H, Okita K, Shirai M. A change in PBP1 is involved in amoxicillin resistance of clinical isolates of Helicobacter pylori. J Antimicrob Chemother. 2002;50:849-856.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 55]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
51.  Rimbara E, Noguchi N, Kawai T, Sasatsu M. Mutations in penicillin-binding proteins 1, 2 and 3 are responsible for amoxicillin resistance in Helicobacter pylori. J Antimicrob Chemother. 2008;61:995-998.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 58]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
52.  Matteo MJ, Granados G, Olmos M, Wonaga A, Catalano M. Helicobacter pylori amoxicillin heteroresistance due to point mutations in PBP-1A in isogenic isolates. J Antimicrob Chemother. 2008;61:474-477.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 40]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
53.  Godoy AP, Reis FC, Ferraz LF, Gerrits MM, Mendonça S, Kusters JG, Ottoboni LM, Ribeiro ML, Pedrazzoli J Jr. Differentially expressed genes in response to amoxicillin in Helicobacter pylori analyzed by RNA arbitrarily primed PCR. FEMS Immunol Med Microbiol. 2007;50:226-230.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
54.  Nikaido H. Multidrug efflux pumps of gram-negative bacteria. J Bacteriol. 1996;178:5853-5859.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Kutschke A, de Jonge BL. Compound efflux in Helicobacter pylori. Antimicrob Agents Chemother. 2005;49:3009-3010.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 50]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
56.  Kim JJ, Reddy R, Lee M, Kim JG, El-Zaatari FA, Osato MS, Graham DY, Kwon DH. Analysis of metronidazole, clarithromycin and tetracycline resistance of Helicobacter pylori isolates from Korea. J Antimicrob Chemother. 2001;47:459-461.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 119]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
57.  Brodersen DE, Clemons WM, Carter AP, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell. 2000;103:1143-1154.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 663]  [Cited by in F6Publishing: 600]  [Article Influence: 25.0]  [Reference Citation Analysis (0)]
58.  Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001;65:232-260; second page, table of contents.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2824]  [Cited by in F6Publishing: 2403]  [Article Influence: 104.5]  [Reference Citation Analysis (0)]
59.  Gerrits MM, Berning M, Van Vliet AH, Kuipers EJ, Kusters JG. Effects of 16S rRNA gene mutations on tetracycline resistance in Helicobacter pylori. Antimicrob Agents Chemother. 2003;47:2984-2986.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 55]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
60.  Nonaka L, Connell SR, Taylor DE. 16S rRNA mutations that confer tetracycline resistance in Helicobacter pylori decrease drug binding in Escherichia coli ribosomes. J Bacteriol. 2005;187:3708-3712.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 36]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
61.  Wu JY, Kim JJ, Reddy R, Wang WM, Graham DY, Kwon DH. Tetracycline-resistant clinical Helicobacter pylori isolates with and without mutations in 16S rRNA-encoding genes. Antimicrob Agents Chemother. 2005;49:578-583.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 52]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
62.  Trieber CA, Taylor DE. Mutations in the 16S rRNA genes of Helicobacter pylori mediate resistance to tetracycline. J Bacteriol. 2002;184:2131-2140.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 118]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
63.  Lawson AJ, Elviss NC, Owen RJ. Real-time PCR detection and frequency of 16S rDNA mutations associated with resistance and reduced susceptibility to tetracycline in Helicobacter pylori from England and Wales. J Antimicrob Chemother. 2005;56:282-286.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 39]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
64.  Trieber CA, Burkhardt N, Nierhaus KH, Taylor DE. Ribosomal protection from tetracycline mediated by Tet(O): Tet(O) interaction with ribosomes is GTP-dependent. Biol Chem. 1998;379:847-855.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 53]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]