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

Goldstein, Beth P.; Vidal-Plana, Ramon R.; Cavalleri, B.; Zerilli, L. F.; G, Carniti; Silvestri, L. G.

doi:10.1099/00221287-100-2-283

Cited by 21 publications

(7 citation statements)

References 31 publications

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“…26 Nitrofurantoin has also been reported to possess a novel mechanism that does not require the production of reactive metabolites by bacterial reductases 8 , . 27 Based on these results and the fact that the degree of reduction required differs, we speculate that the nitroreduction of nitrofurantoin requires the interaction of one or more putative H. pylori nitroreductases that are also required for high level metronidazole resistance.…”

Section: Discussionmentioning

confidence: 83%

Nitrofurantoin quadruple therapy for Helicobacter pylori infection: effect of metronidazole resistance

Graham

Saeed

Hoffman

et al. 2001

Aliment Pharmacol Ther

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INTRODUCTIONMetronidazole resistance has increased world-wide, ranging from less than 10% to greater than 80% among different geographical regions.1 Increasing antimicrobial resistance has resulted in a search for alternative antimicrobial agents, such as nitrofurantoin or furazolidone, especially for use in areas with a high prevalence of metronidazole resistance. By 1987, Helicobacter pylori had been shown to be susceptible to nitrofurantoin and nitrofurantoin was one of the ®rst drugs tried for H. pylori eradication.2 Clinical studies showed that both nitrofurantoin monotherapy and the combination of nitrofurantoin and bismuth were ineffective for the treatment of H. pylori infections.3, 4, 5 In retrospect, these ®nding were not unexpected because it is now recognized that monotherapies and dual therapies with an antibiotic and bismuth are not clinically useful for H. pylori infection.

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Section: Discussionmentioning

confidence: 83%

Nitrofurantoin quadruple therapy for Helicobacter pylori infection: effect of metronidazole resistance

Graham

Saeed

Hoffman

et al. 2001

Aliment Pharmacol Ther

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“…The mechanism by which a molecule such as MEV might induce cross-links is not imme-280 B. P. GOLDSTEIN AND OTHERS diately obvious. Our studies of MEV (Goldstein et al, 1977) and work on other nitroheterocyclic drugs (McCalla et al, 1970;Ings et al, 1974) indicate that reactive compounds are evolved, within sensitive micro-organisms, by reduction of the nitro-drugs to their nitroso-and hydroxylamino-derivatives. Such reactive compounds might induce crosslinking indirectly (Fishbein, Flamm & Falk, 1970;Bautz Freese et al, 1967).…”

Section: ~6 9mentioning

confidence: 82%

“…Such reactive compounds might induce crosslinking indirectly (Fishbein, Flamm & Falk, 1970;Bautz Freese et al, 1967). On the other hand, we have observed incorporation of 14C-labelled MEV metabolites into the cold TCA-precipitable fraction of treated bacteria (Goldstein et al, 1977) and another nitroimidazole, metronidazole, reportedly bound to DNA and proteins in Trichomonas vaginalis on metabolic activation (Ings et al, 1974). In the case of MEV, it is possible that oxidation of the vinyl moiety to the epoxide could provide a second reactive site on the molecule, allowing it to bridge two DNA strands (a suggestion made by M. Calvin).…”

Section: ~6 9mentioning

confidence: 98%

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

Goldstein

Nielsen

Berti

et al. 1977

Journal of General Microbiology

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S U M M A R YThe antimicrobial drug 1-methyl-2-nitro-~-vinylimidazole (MEV) preferentially bjocked DNA synthesis, was mutagenic and induced coliphage h in Escherichia coli. The antibacterial effects of MEV are the consequences of repairable damage to DNA, as shown by hypersensitivity of recA and uvr strains to MEV and related drugs, stimulation by MEV of DNA turnover which was dependent on the product of the uvrA gene, and the presence of cross-links in DNA from MEV-treated bacteria.

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“…Simple inter- calating agents that do not react covalently with DNA (hycanthone and ICR 191) show a limited differential inhibition. Several known premutagens with nitro groups (1-methyl-2-nitro-5-vinylimidazole, nitrofurantoin, nitrofurazone, and 4nitroquinoline-N-oxide) are active in the rec assay in the absence of externally supplied metabolic activation, indicating that microbial nitroreductases are able to produce ultimate mutagens, detected as DNA-damaging agents (4,15,16). A strong limitation of the rec assay is the lack of a protocol for efficient metabolic activation of premutagens other than nitro compounds.…”

Section: Resultsmentioning

confidence: 99%

Bacillus subtilis "rec assay" test with isogenic strains

Mazza¹

1982

Appl Environ Microbiol

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The Bacillus subtilis "rec assay" test, widely used for the detection of DNAdamaging agents, was studied in detail, using an isogenic set of strains carrying different mutations in repair or recombination functions or both. recE4 and rec45 mutations turned out to confer on the cells the highest sensitivity to known mutagens. The recE4 strain and its isogenic rec+ strain have been tested and validated by several rec assay procedures for preferential killing by known DNAdamaging agents. The use of purified spores of the tester strains offers advantages for standardization of the assay. Recombination-and repair-deficient mutants in bacteria are more sensitive, compared with wild-type cells, to the killing action of radiation and DNA-damaging agents. Different chemical damages on DNA are repaired through cellular recombination-repair functions. Based on this relation, a simple assay for screening chemical mutagens of the DNA-damaging type was devised in salmonella, in deep rough strains without DNA excision repair (1) in Escherichia coli, using polA strains (14, 21, 22), and in Bacillus subtilis, with rec mutants (9). Of the repair tests, the most extensively used is that involving B. subtilis rec mutants, called the "rec assay" (9). Substances showing an increased lethal effect on rec mutants versus parental cells may damage cellular DNA and generally turn out to be mutagens. Although the rec assay is not a mutation assay, it is very useful, in addition to mutagenic assays, for preliminary screening programs (6, 8-10, 13, 18, 19). In this paper the identification of the mutations in repair and in recombination, conferring on B. subtilis cells the widest sensitivity spectra for typical chemical mutagens, is described, using an isogenic set of strains. Several rec assay procedures for the measurement of the DNA-damaging activity of chemicals are described in detail. MATERIALS AND METHODS Bacterial strains. The origin and genotypes of the B. subtilis strains used, deficient in different repair or recombination functions or both, are listed in Table 1.

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

Cited by 21 publications

References 31 publications

Nitrofurantoin quadruple therapy for Helicobacter pylori infection: effect of metronidazole resistance

Nitrofurantoin quadruple therapy for Helicobacter pylori infection: effect of metronidazole resistance

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

Bacillus subtilis "rec assay" test with isogenic strains

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