Trends in Microbiology
Volume 10, Issue 8, 1 August 2002, Pages 370-375
Journal home page for Trends in Microbiology

Opinion
Is the molecular basis of metronidazole resistance in microaerophilic organisms understood?

https://doi.org/10.1016/S0966-842X(02)02405-8Get rights and content

Abstract

Metronidazole is an antibiotic that has been effective against many microaerophilic microorganisms with importance in medicine and animal husbandry. The development of increasing resistance against current treatments by many of these organisms has created an urgent need to establish the molecular bases of resistance, knowledge which will help to develop novel diagnostic methods and identify new therapeutic targets. Significant progress has been made in understanding resistance to this antibiotic in the human pathogens Helicobacter pylori and, to a lesser extent, Campylobacter spp. However, insufficient knowledge of the physiology and genetics of these and other related bacteria has led to investigations based on hypotheses that themselves must be established more thoroughly. This review presents the status of our current knowledge of metronidazole resistance and outlines reasons to explain some of the conflicting evidence and controversy in the interpretation of results in this area.

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

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