Interaction of metronidazole with DNA repair mutants of Escherichia coli

Abstract

Anaerobic conditions are required both for the bactericidal effect of metronidazole and for its metabolic transformation to acetamide. These phenomena appear to be related in that the log of the surviving fraction of bacteria susceptible to metronidazole varies linearly with the amount of metronidazole converted to acetamide (1, 9). The most parsimonious explanation for this kinetic relationship is that anaerobic bacteria catalyze the conversion of metronidazole to a labile, partially reduced intermediate which then has one of several possible fates. It may interact, for example, with water to form acetamide or, alternatively, with a bacterial macromolecule to initiate the bactericidal effect (1). This hypothesis suggests that the concentration of the proposed intermediate, M*, determines both the rate of formation of acetamide and the damage to a bacterial macromolecule which, if not repaired, becomes lethal (Fig. 1).Although the chemical nature of M* is not known, its relative concentration over time, and hence the cell's exposure to it, can be inferred from the relative amounts of acetamide that accumulate. The model also enables one to distinguish between two mechanisms of resistance, one that is due to a decreased formation of the reactive form of metronidazole and another that is due to an increased resistance of the bacterial target.The first mechanism, a decreased formation of the partially reduced, reactive form of metronidazole, appears to be responsible for the increased resistance of a clinical isolate of Bacteroides fragilis (4, 9). The relation between bacterial survival and acetamide accumulation for this strain is the same as that for a normally susceptible strain of B. fragilis (9). This suggests that the two strains are equally susceptible to metronidazole's reactive metabolite and that the reactive * Corresponding author. metabolite merely forms more slowly in the resistant strain. This explanation is supported by the finding that nitroreductase activity, which is presumably responsible for the formation of metronidazole's active form, is decreased in the more resistant strain (9, 15).A kinetic approach based on the model in Fig.

Nitroimidazoles for the Treatment of TB: Past, Present and Future

“…However, in the presence of transition elements, such as iron or copper, which are present in the cell bound to a variety of proteins, superoxide reacts with hydrogen peroxide produced during oxidative metabolism to form hydroxyl radical by the Haber–Weiss reaction, which in turn is a potent agent of DNA damage causing DNA fragmentation thereby inhibiting DNA synthesis. This process is thought to be responsible for the cidal activity of metronidazole [10,42,46] and, as a result, mutants in DNA repair pathways are hypersensitive to metronidazole [47,48]. …”

Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis

“…The critical targets that mediate the actions of nitro drugs are incompletely understood. Irreparable DNA damage is important in bacteria [12] and DNA damage also occurs in protozoa [13], but the importance of this mechanism relative to others remains to be shown in Giardia [13]. For example, nitro drugs can act as an energy trap for reducing equivalents generated by critical reductases, thereby compromising the redox and energy metabolism in G. lamblia and other protozoa [10,11,72].…”

“…Several target proteins of Mz have been identified by two-dimensional gel electrophoresis in E. histolytica (thioredoxin, thioredoxin reductase, superoxide dismutase, and purine nucleoside phosphorylase) [10] and G. lamblia (including thioredoxin reductase, giardins, branched-chain amino acid transferase, and pyruvate phosphate dikinase) [11]. In bacteria and protozoa, 5-NI drugs can also cause DNA damage [12,13], but the importance of this mechanism for antigiardial activity remains to be determined [13]. A different nitro-heterocyclic compound (NBDHEX) with activity against G.…”

Effect of different nitroheterocyclic compounds on aerobic, microaerophilic, and anaerobic bacteria

“…A lack of the activating enzyme may also be responsible for the resistance of strains E. coli 10432/84 and S. typhimurium 2400/80 and 5568/84. It is postulated that the reduction of the nitro group of the antibacterial substance may lead to toxic intermediates which are able to damage the bacterial DNA (9,20,28). The resistance of certain strains of microaerophilic campylobacter isolates to these compounds ( (20), which renders these bacteria ( …”

“…Another possible explanation for the pronounced susceptibility of strains TA-1538 and TA-98 could be their lack of a DNA repair system, so that even minor DNA damage may have bactericidal effects. Similar repair-deficient mutants of E. coli also have an increased susceptibility to metronidazole (28).…”