Whos Winning the War? Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori

Jones, Kathleen R.; Heon, Jeong; Merrell, D. Scott

doi:10.2174/157488508785747899

Cited by 30 publications

(26 citation statements)

References 172 publications

(201 reference statements)

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“…Considering the increasing resistance observed among H. pylori strains worldwide (38,81), therapeutic options are becoming significantly limited. Therefore, the aim of the present study was to evaluate the antimicrobial activity of OAKs against H. pylori.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Antibacterial Activity of Acyl-Lysyl Oligomers againstHelicobacter pylori

Makobongo

Kovachi

Gancz

et al. 2009

Antimicrob Agents Chemother

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The gastric pathogen Helicobacter pylori has developed resistance to virtually all current antibiotics; thus, there is a pressing need to develop new anti-H. pylori therapies. The goal of this work was to evaluate the antibacterial effect of oligo-acyl-lysyl (OAK) antimicrobial peptidomimetics to determine if they might represent alternatives to conventional antibiotic treatment of H. pylori infection. A total of five OAK sequences were screened for growthinhibitory and/or bactericidal effects against H. pylori strain G27; four of these sequences had growth-inhibitory and bactericidal effects. The peptide with the highest efficacy against strain G27, C 12 K-2␤ 12 , was selected for further characterization against five additional H. pylori strains (26695, J99, 7.13, SS1, and HPAG1). C 12 K-2␤ 12 displayed MIC and minimum bactericidal concentration (MBC) ranges of 6.5 to 26 M and 14.5 to 90 M, respectively, across the six strains after 24 h of exposure. G27 was the most sensitive H. pylori strain (MIC ‫؍‬ 6.5 to 7 M; MBC ‫؍‬ 15 to 20 M), whereas 26695 was the least susceptible strain (MIC ‫؍‬ 25 to 26 M; MBC ‫؍‬ 70 to 90 M). H. pylori was completely killed after 6 to 8 h of incubation in liquid cultures containing two times the MBC of C 12 K-2␤ 12 . The OAK demonstrated strong in vitro stability, since efficacy was maintained after incubation at extreme temperatures (4°C, 37°C, 42°C, 50°C, 55°C, 60°C, and 95°C) and at low pH, although reduced killing kinetics were observed at pH 4.5. Additionally, upon transient exposure to the bacteria, C 12 K-2␤ 12 showed irreversible and significant antibacterial effects and was also nonhemolytic. Our results show a significant in vitro effect of C 12 K-2␤ 12 against H. pylori and suggest that OAKs may be a valuable resource for the treatment of H. pylori infection.Helicobacter pylori is a microaerophilic gram-negative bacterium that colonizes the gastric mucosa. It is known to be a principal gastric pathogen of humans and is associated with the development of gastritis, gastric ulcers, duodenal ulcers, and gastric cancer (46,55,56,60). Approximately half of the world's population is infected with H. pylori (79). Thus, the bacterium poses a significant public health problem, which is further compounded by the fact that H. pylori has developed antimicrobial resistance to virtually all current antibiotics, a phenomenon that is hampering efforts to treat the infection (40, 51).Since the original isolation of H. pylori in the early 1980s, treatment of the bacterial infection has undergone a significant evolutionary development from initial monotherapy to dual, triple, and in more recent trials quadruple therapy (8, 18). Current treatment strategies employ combination therapy, since single-antibiotic therapy often results in failure to eradicate the infection (21). The highest H. pylori eradication rates have been reported with triple therapy, which involves the utilization of two antibiotics in combination with bismuth or a proton pump inhibitor, PPI (34,44). Amoxicillin (amoxicil...

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Section: Discussionmentioning

confidence: 99%

“…However, high rates of resistance have been reported for people with a history of metronidazole treatment (49). Given the immense challenge in rising antimicrobial resistance (38), there is an enormous need for new antibiotics for the treatment of H. pylori infection.…”

mentioning

confidence: 99%

In Vitro Antibacterial Activity of Acyl-Lysyl Oligomers againstHelicobacter pylori

Makobongo

Kovachi

Gancz

et al. 2009

Antimicrob Agents Chemother

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“…For enterococci, it has been shown that MICs of linezolid-resistant isolates are highly correlated with the percentage of rRNA cistrons mutated (237). In a way similar to the rRNA case, the FQs which have dual targets in standard pathogens have only a single target (DNA gyrase) in both Mycobacterium tuberculosis and H. pylori (160) and do yield to single-step resistance (178,195).…”

Section: The Multitarget Hypothesismentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,155

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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“…Clarithromycin acts by binding to the peptidyltransferase region of 23S rRNA, thereby inhibiting protein synthesis (Gerrits et al, 2006;Jones et al, 2008). The resistance to clarithromycin in H. pylori has been shown to be due to point mutations in the peptidyltransferase region of domain V of the 23S rRNA.…”

Section: Introductionmentioning

confidence: 99%

Resistance to clarithromycin and genotypes in Helicobacter pylori strains isolated in Sicily

Fasciana

Calà

Bonura

et al. 2015

Journal of Medical Microbiology

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The resistance of Helicobacter pylori strains to clarithromycin is increasing in several developed countries and their association with a genetic pattern circulation has been variously explained as related to different geographical areas. In this study we have reported: the prevalence of the resistance of H. pylori, isolated in Sicily, to clarithromycin; the principal point of mutation associated with this resistance; and the more frequent association between resistance to clarithromycin and cagA, the EPIYA motif, and the vacA and oipA genes. Resistance to clarithromycin was detected in 25 % of cases, the main genetic mutation involved being A2143G. The cagA gene was present in 48 % of cases and the distribution of the EPIYA motif was: ABC in 35 cases; ABCC in 8 cases; ABCCC in 2 cases; ABC-ABCC in 2 cases; and ABC-ABCC-ABCCC in 1 case. Regarding the vacA allele, an s1i1m1 combination was detected in 35 % of cases, s1i1m2 in 12 %, s1i2m2 in 12 %, s2i2m2 in 40 %, and a double s1m1-m2 mosaic in 1 % of cases. The status of the oipA gene was 'off' in 45 % of cases and 'on' in 55 %. Resistance to clarithromycin was found to be high in Sicily, but no correlation was found among resistance to clarithromycin, the vacA gene and oipA status; a higher correlation was observed between resistant strains and cagA-negative strains.

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Whos Winning the War? Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori

Cited by 30 publications

References 172 publications

In Vitro Antibacterial Activity of Acyl-Lysyl Oligomers againstHelicobacter pylori

In Vitro Antibacterial Activity of Acyl-Lysyl Oligomers againstHelicobacter pylori

Challenges of Antibacterial Discovery

Resistance to clarithromycin and genotypes in Helicobacter pylori strains isolated in Sicily

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