The mode of action of metronidazole in Trichomonas vaginalis and other micro-organisms

Ings, R. M. J.; McFadzean, James A.; Ormerod, W.E.

doi:10.1016/0006-2952(74)90362-1

Cited by 194 publications

(89 citation statements)

References 10 publications

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“…However, the anaerobic cytotoxicity is generally considered to be due to a reduced species, the concentration of which is governed by the rate of its formation (i.e. reduction) which depends upon a reduction-rate-generated concentration gradient (Ings et al, 1974) and its relative stability. Since the data shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

Knox¹,

Knight²,

Edwards³

1981

Br J Cancer

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Summary.-An electrolytic reduction system has been developed to model the cytotoxic action of a range of nitroimidazole drugs against DNA in hypoxic cells or anaerobic microorganisms. The degree of damage induced by these drugs (measured as the release of [14C]-dT from DNA) and their relative rates of reduction have been correlated with their redox potentials. The results show that the correlation of druginduced damage and electron affinity is related to the amount of drug reduced, and supports the hypothesis that at the molecular level the cytotoxic mechanism of reduced nitroimidazoles is identical in hypoxic mammalian cells, bacteria and protozoa.HYPoxic CELLS are more resistant to ionizing radiation than well oxygenated ones, and their presence in human tumours may lead to the failure of radiotherapy. In addition to their ability as radiosensitizers, nitroimidazoles are selectively cytotoxic to hypoxic cells (Adams et al., 1978). The basis of structure-activity relationships in the development of electron-affinic nitroheterocyclic hypoxic cell radiosensitizers is a linear correlation of the type: -log C = bo + bi E + b2 log P + b3 (log P)2 where C is the drug concentration required to cause a specific and relevant biological effect, E is the electron affinity, usually expressed as the one-electron redox potential (E71), and P is the lipidwater partition coefficient of the drug. Adams et al. (1979a,b) have shown that lipophilicity has a negligible effect on radiosensitizing efficiency and cytotoxicity. Thus coefficients b2 and b3 may be omitted, yielding the simplified equation

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Section: Discussionmentioning

confidence: 99%

Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

Knox¹,

Knight²,

Edwards³

1981

Br J Cancer

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“…Uptake of metronidazole for long periods by Trichomonas is explained as a consequence of its metabolism to derivatives (35,36). Metronidazole cannot be reoxidized when it is reduced by dithionite (13), probably because the imidazole ring is cleaved under these conditions (37).…”

Section: Discussionmentioning

confidence: 99%

“…Photoreduction of other nitroaromatic compounds in vitro has been shown to result in the formation of hydroxylamines (28,38). Hydroxylamine products, which could be formed through the reduction of metronidazole by four or six electrons, are generally considered to be the active forms of the drug in anaerobes (13,35). The scheme in Fig.…”

Section: Discussionmentioning

confidence: 99%

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A rapid procedure for selective enrichment of photosynthetic electron transport mutants.

Schmidt¹,

Matlin²,

Chua³

1977

Proc. Natl. Acad. Sci. U.S.A.

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Metronidazole (2-methyl-5-nitroimidazole-1-ethanol) is shown to be effective for the selective enrichment of mutants of Chlamydomonas reinhardtii that possess impaired photosynthetic electron transport. More than 99.91% of -type cells are killed when incubated in the presence of 6-10 mM metronidazole for 24 hr under illumination of 7500 lux. Survival of wild-type cells in darkness and of mutants that are blocked at different steps in photosynthetic electron transport is nearly 100% when incubated in the presence of the drug under identical conditions.The toxicity of metronidazole is demonstrated to depend upon its reduction by photosynthetic electron transport. Light-dependent oxygen utake mediated by metronidazole is shown to require active photosystem I in vitro and in vivo. Ferredoxin is necessary for metronidazole reduction by thylakoid membrane fractions enriched in photosystem I activity. We propose that the toxicity of metronidazole is due to the formation of lethal derivatives of the drug or to the accumulation of hydrogen peroxide, which could occur upon autooxidation of metronidazole reduced by one electron. Preparation of Thylakoid Membrane Fractions. Thylakoid membranes were purified as previously described (S). For assays of photosynthetic electron transport activities, the thylakoids were suspended in 25 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes)-KOH (pH 7.5).Preparation of PS I Particles. Preparations of thylakoid membrane particles enriched in PS I activities were obtained by digitonin treatment of crude membranes (10). Wild-type cells (8 X 108) were harvested by centrifugation at 2500 X g and washed with 10 mM potassium phosphate (pH 7.0)/20 mM KCI/2.5 mM MgCl2. Washed cells were resuspended in 40 ml of the same buffer and were disrupted at 00 by sonication for 1 min with a Heat-System Ultrasonics sonifier. Pellets obtained by centrifugation at 48,000 X gma. for 15 min were resuspended in 15 ml of the buffer and homogenized with a motor-driven Teflon pestle. The thylakoids (300 ,g of chlorophyll per ml) were treated with 0.5% (wt/vol) RESULTSMetronidazole (2-methyl-5-nitroimidazole-1-ethanol) is widely used clinically for the treatment of infections of anaerobic bacteria and protozoa (11). It is a nitroheterocyclic compound possessing a low redox potential (-325 mV at pH 6.9) (12). The toxicity of metronidazole is thought to depend upon reduction 610

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“…Inside the protozoan cell, the reduction of nitro group of metronidazole occurs by reduced ferredoxin or flavodoxin to form a reactive nitro radical. The cytotoxic influences on different protozoa species inflicted by metronidazole are believed to be involved inhibition of nucleic acid synthesis or damage the DNA of parasitic cell (Ings et al 1974).…”

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confidence: 99%

Anti-Pentatrichomonas hominis activity of newly synthesized benzimidazole derivatives — in vitro studies

Chomicz¹,

Padzik²,

Laudy³

et al. 2009

Acta Parasitologica

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Pentatrichomonas hominis, a parasitic protozoan often detected in human diarrheic stools, is the cause of severe morbidity in newborns and children, particularly in tropical zones. The flagellate is resistant to many disinfectants and anti-protozoan drugs. Therefore in this study we have synthesized three novel 4,5,6,7-tetrabromobenzimidazole (TBBI) derivatives carrying a polyfluoroalkyl substituent in position 2 of the benzimidazole scaffold, namely 2-trifluoromethyl-TBBI (CF 3 -TBBI), 2-nonafluorobutyl-TBBI (C 4 F 9 -TBBI), and 2-nonadecafluorononyl-TBBI (C 9 F 19 -TBBI), that next we tested for their in vitro activity against P. hominis. Widely applied anti-protozoal drug, metronidazole as a reference was used. All the investigated agents were added to 24 h P. hominis cultures; each of them was administered at three different concentrations. Number of the moving trichomonads was determined and compared with the control cultures. Different anti-trichomonal activity occurred depending on a kind of compound and its concentration. C 4 F 9 -TBBI was the most effective TBBI derivative tested: the agent, at the highest concentration 24.2 µg/ml, after 72 h reduced the number of viable trichomonads to 44.3%; C 9 F 19 -TBBI, at the concentration 24 µg/ml reduced the number of the flagellates to 58.5%. Paradoxically, metronidazole after the same time given at the highest concentration increased trophozoite counts by 464.6% in comparison with the control cultures (100%).

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The mode of action of metronidazole in Trichomonas vaginalis and other micro-organisms

Cited by 194 publications

References 10 publications

Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

A rapid procedure for selective enrichment of photosynthetic electron transport mutants.

Anti-Pentatrichomonas hominis activity of newly synthesized benzimidazole derivatives — in vitro studies

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