Trends in Microbiology
OpinionIs the molecular basis of metronidazole resistance in microaerophilic organisms understood?
Section snippets
Potential mechanisms of Mtr resistance
To establish the molecular basis of antibiotic resistance in organisms of the same species is to understand how they modify their molecular make-up with changes that become permanent to overcome the challenge of an antibiotic. Thus, allowing for intraspecific biological variability, an explanation of resistance correlates phenotypic and functional characteristics with molecular properties at the DNA, RNA and protein levels. Potential mechanisms of Mtr resistance studied in H. pylori include
RdxA nitroreductase: its role in Mtr resistance
The fundamental discovery that Mtr resistance in H. pylori can result from the loss of activity of an oxygen-independent NADPH nitroreductase encoded by the gene rdxA marked the beginning of a renewed and intense interest in gaining a full understanding of the causes of resistance to this drug. Initially, mutational inactivation of rdxA was designated the cause of naturally acquired Mtr resistance in H. pylori [26], and various features of RdxA (Fig. 2), the polypeptide it encodes, were
FrxA nitroreductase and Mtr resistance
Investigations of the role in resistance of other enzymes potentially capable of reducing Mtr yielded mixed results 23., 24., 25.. The discovery of frameshift mutations in the gene frxA, encoding an NAD(P)H:flavin oxidoreductase, suggested a potential role for FrxA in Mtr resistance in H. pylori 30., 38.. Confirmation was obtained by transformation of MtrS strains with the mutated frxA, and by inactivation of this gene in sensitive strains. Also, an E. coli resistant strain transformed with the
The importance of definitions
Historically, definitions of microbial resistance to antibiotics have been operational definitions. They describe agreed experimental protocols that serve to indicate the expected efficacy of drugs against specific pathogenic agents; these protocols are revised and improved with time. Under similar growth conditions, two experimental parameters that could affect the mutation frequency are the density of the inoculum and the concentration of Mtr used to select resistant strains. Authors
Final comments
Interesting lessons can be learned from the significant advances made in understanding the resistance of H. pylori and, to a lesser extent, of Campylobacter spp. to Mtr. The involvement of rdxA, frxA and their gene products in the resistance of H. pylori to Mtr appears established, but it is much less clear that these are the only genes and enzymes responsible for the resistant phenotypes. The experience acquired in past studies should help to avoid placing too great an emphasis on some genes
References (41)
Reduction of nitroimidazoles and DNA damage
Biochem. Pharmacol.
(1986)DNA breakage due to metronidazole treatment
Mutat. Res.
(2001)Metronidazole susceptibility in Helicobacter pylori
Gastroenterology
(1999)- et al.
Molecular basis of metronidazole resistance in pathogenic bacteria and protozoa
Drug Resist. Update
(1999) - et al.
Metronidazole resistance in Helicobacter pylori
Int. J. Antimicrob. Agents
(2002) Isolation of a genetic locus associated with metronidazole resistance in Helicobacter pylori
Biochem. Biophys. Res. Commun.
(1997)Oxidases and reductases are involved in metronidazole sensitivity in Helicobacter pylori
Int. J. Biochem. Cell Biol.
(2001)Quantitative RT-PCR analysis of multiple genes encoding putative metronidazole nitroreductases from Helicobacter pylori
Int. J. Antimicrob. Agents
(2000)Potential involvement of several nitroreductases in metronidazole resistance in Helicobacter pylori
Arch. Biochem. Biophys.
(2001)Nitroimidazole drugs – action and resistance mechanisms I. Mechanisms of action
J. Antimicrob. Chemother.
(1993)
The mode of action of metronidazole in Helicobacter pylori: futile cycling or reduction?
J. Antimicrob. Chemother.
Metronidazole resistance and microaerophily in Campylobacter species
Arch. Microbiol.
Metronidazole activation is mutagenic and causes DNA fragmentation in Helicobacter pylori and Escherichia coli containing a cloned H. pylori rdxA+ (nitroreductase) gene
J. Bacteriol.
Microbial ecology and treatment of Helicobacter pylori infections: review
J. Chemother.
Mechanisms and clinical significance of metronidazole resistance in Helicobacter pylori
Scand. J. Gastroenterol.
Metronidazole uptake in Helicobacter pylori
Can. J. Microbiol.
Helicobacter pylori uptake and efflux: basis for intrinsic susceptibility to antibiotics in vitro
Antimicrob. Agents Chemother.
Isolation of the Helicobacter pylori recA gene and involvement of the recA region in resistance to low pH
Infect. Immun.
Insertion of mini-IS605 and deletion of adjacent sequences in the nitroreductase (rdxA) gene cause metronidazole resistance in Helicobacter pylori NCTC11637
Antimicrob. Agents Chemother.
Redox potential and oxygen concentration as factors in the susceptibility of Helicobacter pylori to nitroheterocyclic drugs
J. Antimicrob. Chemother.
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