The Mechanism of Action of Nitro-heterocyclic Antimicrobial Drugs. Primary Target of 1-Methyl-2-nitro-5-vinylimidazole is DNA

Goldstein, Beth P.; Nielsen, Erik; Berti, Marisa; Bolzoni, G; Silvestri, L. G.

doi:10.1099/00221287-100-2-271

Cited by 16 publications

(11 citation statements)

References 9 publications

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“…The second antibiotic, metronidazole is a 5-nitroimidazole derivative, and in order to produce an antimicrobial effect, the drug has to be transported into the cell, where it is chemically reduced into its active components (free radical anion, superoxide, nitroso free radical, hydroxylamine derivative) The exact mechanism of cytotoxicity is not fully understood, but the most widely held explanation is that the reactive metabolite(s) reacts with the target species' DNA (44)(45)(46)(47). Due to the necessity of metronidazole reduction for it to produce an antimicrobial effect, the majority of susceptible organisms are strictly anaerobic (3,48).…”

Section: Discussionmentioning

confidence: 99%

Effects of Antibiotics on Bacterial Species Composition and Metabolic Activities in Chemostats Containing Defined Populations of Human Gut Microorganisms

Newton

Macfarlane

2013

Antimicrob Agents Chemother

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The composition and metabolic activities of the human colonic microbiota are modulated by a number of external factors, including diet and antibiotic therapy. Changes in the structure and metabolism of the gut microbiota may have long-term consequences for host health. The large intestine harbors a complex microbial ecosystem comprising several hundreds of different bacterial species, which complicates investigations on intestinal physiology and ecology. To facilitate such studies, a highly simplified microbiota consisting of 14 anaerobic and facultatively anaerobic organisms (Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium pseudolongum, Bifidobacterium adolescentis, Clostridium butyricum, C. perfringens, C. bifermentans, C. innocuum, Escherichia coli, Enterococcus faecalis, Enterococcus faecium, Lactobacillus acidophilus) was used in this investigation. Ampicillin [9.2 g (ml culture) ؊1 ] was added to two chemostats operated at different dilution rates (D; 0.10 h ؊1 and 0.21 h ؊1 ), and metronidazole [76.9 g (ml culture) ؊1 ] was added to a third vessel (D ‫؍‬ 0.21 h ؊1 ). Perturbations in bacterial physiology and metabolism were sampled over a 48-h period. Lactobacillus acidophilus and C. bifermentans populations did not establish in the fermentors under the imposed growth conditions. Ampicillin resulted in substantial reductions in bacteroides and C. perfringens populations at both dilution rates. Metronidazole strongly affected bacteroides communities but had no effect on bifidobacterial communities. The bacteriostatic effect of ampicillin on bifidobacterial species was growth rate dependent. Several metabolic activities were affected by antibiotic addition, including fermentation product formation and enzyme synthesis. The growth of antibiotic-resistant bifidobacteria in the large bowel may enable them to occupy ecological niches left vacant after antibiotic administration, preventing colonization by pathogenic species.

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Section: Discussionmentioning

confidence: 99%

Effects of Antibiotics on Bacterial Species Composition and Metabolic Activities in Chemostats Containing Defined Populations of Human Gut Microorganisms

Newton

Macfarlane

2013

Antimicrob Agents Chemother

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“…Minimal inhibitory concentrations (mic.) for E. coli K I 2 strains were determined as described by Goldstein et al (1977). For strain ~4 7 , the same procedure was used except that bacteria were grown in Penassay broth (Difco).…”

Section: Methodsmentioning

confidence: 99%

“…Although members of this class of drugs differ in a number of properties including their spectrum of antimicrobial activity (Grunberg & Titsworth, 1973 ;Edwards, Dye & Carne, 1973)~ studies of the mechanism of action of nitrofurazone (McCalla, Reuvers & Kaiser, I 970), metronidazole (Ings, McFadzean & Ormerod, 1974) and MEV (Goldstein et al, 1977) suggest that the effective target of all of these drugs is DNA.…”

Section: -Methyl-2-nitro-~-vinylimidazole (Mev)mentioning

confidence: 99%

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The Mechanism of Action of Nitro-heterocyclic Antimicrobial Drugs. Metabolic Activation by Micro-organisms

Goldstein¹,

Vidal-Plana²,

Cavalleri³

et al. 1977

Journal of General Microbiology

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Although the target of the antimicrobial drug 1-methyl-2-nitro-5-vinylimidazole (MEV) has been shown to be DNA (Goldstein et al., 1977) the drug was ineffective in cell-free systems because it was not activated. Both the rate of metabolic activation of MEV and its antibacterial activity were increased when bacteria were grown in limiting oxygen. Mutants of Escherichid coli which were conditionally resistant to nitroimidazoles and nitrofurans were defective in drug activation. The activities of these drugs against E. coli correlated with their rates of metabolism. The antimicrobial spectrum of the drugs appeared to be related to their reducibility by different species.

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“…1 has now been used to characterize metronidazole's target within susceptible bacteria. That DNA is a primary target for metronidazole is suggested by chemical (7,8) and mutagenicity (13,16) studies as well as by the finding (3,5,12) Cultures. The strains of E. coli used are described in Table 1.…”

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Interaction of metronidazole with DNA repair mutants of Escherichia coli

Yeung¹,

Beaulieu²,

McLafferty³

et al. 1984

Antimicrob Agents Chemother

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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.

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The Mechanism of Action of Nitro-heterocyclic Antimicrobial Drugs. Primary Target of 1-Methyl-2-nitro-5-vinylimidazole is DNA

Cited by 16 publications

References 9 publications

Effects of Antibiotics on Bacterial Species Composition and Metabolic Activities in Chemostats Containing Defined Populations of Human Gut Microorganisms

Effects of Antibiotics on Bacterial Species Composition and Metabolic Activities in Chemostats Containing Defined Populations of Human Gut Microorganisms

The Mechanism of Action of Nitro-heterocyclic Antimicrobial Drugs. Metabolic Activation by Micro-organisms

Interaction of metronidazole with DNA repair mutants of Escherichia coli

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