Abstract
Antibiotic resistance in bacteria incurs fitness cost, but compensatory mechanisms may ameliorate the cost and sustain the resistance even under antibiotics-free conditions. The aim of this study was to determine compensatory mechanisms of antibiotic resistance in H. pylori. Five strains of levofloxacin-sensitive H. pylori were induced in vitro to develop resistance. In addition, four pairs of metronidazole-sensitive and -resistant H. pylori strains were isolated from patients carrying dual H. pylori populations that consist of both sensitive and resistant phenotypes. Growth rate, virulence and biofilm-forming ability of the sensitive and resistant strains were compared to determine effects of compensatory response. Proteome profiles of paired sensitive and resistant strains were analyzed by liquid chromatography/mass spectrophotometry (LC/MS). Although there were no significant differences in growth rate between sensitive and resistant pairs, bacterial virulence (in terms of abilities to induce apoptosis and form biofilm) differs from pair to pair. These findings demonstrate the complex and strain-specific phenotypic changes in compensation for antibiotics resistance. Compensation for in vitro induced levofloxacin resistance involving mutations of gyrA and gyrB was functionally random. Furthermore, higher protein translation and non-functional protein degradation capabilities in naturally-occuring dual population metronidazole sensitive-resistant strains may be a possible alternative mechanism underlying resistance to metronidazole without mutations in rdxA and frxA. This may explain the lack of mutations in target genes in ~10% of metronidazole resistant strains.
Highlights
Helicobacter pylori is a common bacterial pathogen that colonize the human stomach and is related to incidence of gastric cancer and peptic ulcer diseases (Parsonnet et al, 1991; Dhar et al, 2003)
Current recommendations for H. pylori treatment include the first line therapy, which is standard triple therapy consisting a combination of proton pump inhibitors (PPI), clarithromycin, and amoxicillin or metronidazole; the second line therapy will be used in the case of treatment failure, in which bismuth-based quadruple therapy or levofloxacin-containing triple therapy are recommended (Malfertheiner et al, 2007)
A proteomic study on metronidazole-resistant H. pylori had examined metabolic changes in the bacteria which reported down- and up-regulation of various proteins including a protein with reductase activity (McAtee et al, 2001)
Summary
Helicobacter pylori is a common bacterial pathogen that colonize the human stomach and is related to incidence of gastric cancer and peptic ulcer diseases (Parsonnet et al, 1991; Dhar et al, 2003). The increasing prevalence of antibiotic resistance in H. pylori is a cause of concern as this is one of the most important causes of therapy failure (Graham and Fischbach, 2010). The antibiotics used to treat H. pylori infection were mainly amoxicillin, clarithromycin, and metronidazole; these would be administered for 10–14 days in combination with an antisecretory drug to increase the pH (Lind et al, 1999). Current recommendations for H. pylori treatment include the first line therapy, which is standard triple therapy consisting a combination of proton pump inhibitors (PPI), clarithromycin, and amoxicillin or metronidazole; the second line therapy will be used in the case of treatment failure, in which bismuth-based quadruple therapy or levofloxacin-containing triple therapy are recommended (Malfertheiner et al, 2007)
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