Metabolism of a 5-nitroimidazole in susceptible and resistant isogenic strains of Bacteroides fragilis

Abstract

We investigated the metabolism of dimetridazole (1,2-dimethyl-5-nitroimidazole) (DMZ) by the resting cell method in a susceptible strain of Bacteroides fragilis and in the same strain containing the nimA gene, which conferred resistance to 5-nitroimidazole drugs. In both cases, under strict anaerobic conditions DMZ was metabolized without major ring cleavage or nitrate formation. However, one of two distinct metabolic pathways is involved, depending on the susceptibility of the strain. In the susceptible strain, the classical reduction pathway of nitroaromatic compounds is followed at least as far as the nitroso-radical anion, with further formation of the azo-dimer: 5,5-azobis-(1,2-dimethylimidazole). In the resistant strain, DMZ is reduced to the amine derivative, namely, 5-amino-1,2-dimethylimidazole, preventing the formation of the toxic form of the drug. The specificity of the six-electron reduction of the nitro group, which is restricted to 4-and 5-nitroimidazole, suggests an enzymatic reaction. We thus conclude that nimA and related genes may encode a 5-nitroimidazole reductase.

Proteomic Analysis of a NAP1 Clostridium difficile Clinical Isolate Resistant to Metronidazole

“…The increased expression is independent of the presence of metronidazole (data not shown). Reduced susceptibility to 5-nitroimidazole drugs has been associated with the presence of a nim -encoded nitroimidazole reductase, which converts 4- or 5-nitroimidazole to 4- or 5-aminoimidazole, avoiding the formation of the toxic nitroso radicals [36], [56]. Therefore, the increased expression of 5-nitroimidazole reductase in CD26A54_S and CD26A54_R may be a factor in the reduced susceptibility and resistance to metronidazole observed in these isolates.…”

Are Sewage Treatment Plants Promoting Antibiotic Resistance?

“…This reductive mechanism appears to be unique to the anaerobes (Narikawa, 1986). Resistance is associated with the nim genes encoding 5-nitroimidazole reductase enzymes located on the chromosome (nimB) or on low-copy self-transmissible plasmids (Carlier et al, 1997). Nitroimidazole reductase acts by removing an electron from the intermediary ferredoxin compound, thus eliminating the drug's trigger mechanism.…”

New Insights into Prevotella Diversity and Medical Microbiology

“…Acquired resistance to metronidazole in anaerobes is usually associated with the presence of a nitroimidazole reductase, encoded by a nim gene. Using ferredoxin as the electron donor, this enzyme converts 4-or 5-nitroimidazoles to 4-or 5-aminoimidazoles, thus avoiding the formation of toxic nitroso radicals, which are the active antibacterial compounds [244,245]. In Bacteroides spp., seven nim genes named nimA-G, which are either plasmid or chromosomally encoded, have been reported [211], while a new nim gene (nimH, accession number FJ969397) has been detected in B. fragilis.…”