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A review on metronidazole: an old warhorse in antimicrobial chemotherapy

  • David Leitsch (a1)


The 5-nitroimidazole drug metronidazole has remained the drug of choice in the treatment of anaerobic infections, parasitic as well as bacterial, ever since its development in 1959. In contrast to most other antimicrobials, it has a pleiotropic mode of action and reacts with a large number of molecules. Importantly, metronidazole, which is strictly speaking a prodrug, needs to be reduced at its nitro group in order to become toxic. Reduction of metronidazole, however, only takes place under very low concentrations of oxygen, explaining why metronidazole is exclusively toxic to microaerophilic and anaerobic microorganisms. In general, resistance rates amongst the pathogens treated with metronidazole have remained low until the present day. Nevertheless, metronidazole resistance does occur, and for the treatment of some pathogens, especially Helicobacter pylori, metronidazole has become almost useless in some parts of the world. This review will give an account on the current status of research on metronidazole's mode of action, metronidazole resistance in eukaryotes and prokaryotes, and on other 5-nitroimidazoles in use.


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Author for correspondence: David Leitsch, E-mail:


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Aldridge, KE, Ashcraft, D, O'Brien, M and Sanders, CV (2003) Bacteremia due to Bacteroides fragilis group: distribution of species, β-lactamase production, and antimicrobial susceptibility patterns. Antimicrobial Agents and Chemotherapy 47, 148153.
Ansell, BR, Baker, L, Emery, SJ, McConville, MJ, Svärd, SG, Gasser, RB and Jex, AR (2017) Transcriptomics indicates active and passive metronidazole resistance mechanisms in three seminal Giardia lines. Frontiers in Microbiology 8, 398.
Binh, TT, Suzuki, R, Trang, TT, Kwon, DH and Yamaoka, Y (2015) Search for novel candidate mutations for metronidazole resistance in Helicobacter pylori using next-generation sequencing. Antimicrobial Agents and Chemotherapy 59, 23432348.
Boreham, PF, Phillips, RE and Shepherd, RW (1988) Altered uptake of metronidazole in vitro by stocks of Giardia intestinalis with different drug sensitivities. Transactions of the Royal Society of Tropical Medicine and Hygiene 82, 104106.
Bradic, M, Warring, SD, Tooley, GE, Scheid, P, Secor, WE, Land, KM, Huang, PJ, Chen, TW, Lee, CC, Tang, P, Sullivan, SA and Carlton, JM (2017) Genetic indicators of drug resistance in the highly repetitive genome of Trichomonas vaginalis. Genome Biology and Evolution 9, 16581672.
Brazier, JS, Stubbs, SLJ and Duerden, BI (1999) Metronidazole resistance among clinical isolates belonging to the Bacteroides fragilis group: time to be concerned? Journal of Antimicrobial Chemotherapy 44, 577582.
Breuil, J, Dublanchet, A, Truffaut, N and Sebald, M (1989) Transferable 5-nitroimidazole resistance in Bacteroides fragilis group. Plasmid 21, 151154.
Carlier, JP, Sellier, N, Rager, MN and Reysset, G (1997) Metabolism of a 5-nitroimidazole in susceptible and resistant isogenic of Bacteroides fragilis. Antimicrobial Agents and Chemotherapy 41, 14951499.
Carter, ER, Nabarro, LE, Hedley, L and Chiodini, PL (2017) Nitroimidazole-refractory giardiasis; a growing problem requiring rational solutions. Clinical and Microbiological Infections. pii: S1198-743X(17)30289-6.
Cerkasovová, A, Cerkasov, J and Kulda, J (1984) Metabolic differences between metronidazole resistant and susceptible strains of Tritrichomonas foetus. Molecular and Biochemical Parasitology 11, 105118.
Chapman, A, Cammack, R, Linstead, R and Lloyd, D (1985) The generation of metronidazole radicals in hydrogenosomes isolated from Trichomonas vaginalis. Journal of General Microbiology 131, 21412144.
Chapman, A, Linstead, DJ and Lloyd, D (1999) Hydrogen peroxide is a product of oxygen consumption by Trichomonas vaginalis. Journal of Biosciences 24, 339344.
Chong, PM, Lynch, T, McCorrister, S, Kibsey, P, Miller, M, Gravel, D, Westmacott, GR and Mulvey, MR, Canadian Nosocomial Infection Surveillance Program (CNISP) (2014) Proteomic analysis of a NAP1 Clostridium difficile clinical isolate resistant to metronidazole. PLoS ONE 9, e82622.
Chow, AW, Patten, V and Bednorz, D (1978) Susceptibility of Campylobacter fetus to twenty-two antimicrobial agents. Antimicrobial Agents and Chemotherapy 3, 416418.
Conrad, MD, Gorman, AW, Schillinger, JA, Fiori, PL, Arroyo, R, Malla, N, Dubey, ML, Gonzalez, J, Blank, S, Secor, WE and Carlton, JM (2012) Extensive genetic diversity, unique population structure and evidence of genetic exchange in the sexually transmitted parasite Trichomonas vaginalis. PLoS Neglected Tropical Diseases 6, e1573.
Cosar, C and Julou, L (1959) The activity of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (R. P. 8823) against experimental Trichomonas vaginalis infections. Annales d l'Inststitut Pasteur 96, 238241.
Crozet, MD, Botta, C, Gasquet, M, Curti, C, Rémusat, V, Hutter, S, Chapelle, O, Azas, N, De Méo, M and Vanelle, P (2009) Lowering of 5-nitroimidazole's mutagenicity: towards optimal antiparasitic pharmacophore. European Journal of Medicinal Chemistry 44, 653659.
Dan, M, Wang, AL and Wang, CC (2000) Inhibition of pyruvate-ferredoxin oxidoreductase gene expression in Giardia lamblia by a virus-mediated hammerhead ribozyme. Molecular Microbiology 36, 447456.
De Francesco, V, Giorgio, F, Hassan, C, Manes, G, Vannella, L, Panella, C, Ierardi, E and Zullo, A (2010) Worldwide H. pylori antibiotic resistance: a systematic review. Journal of Gastrointestinal and Liver Diseases 19, 409414.
De Francesco, V, Bellesia, A, Ridola, L, Manta, R and Zullo, A (2017) First-line therapies for Helicobacter pylori eradication: a critical reappraisal of updated guidelines. Annals of Gastroenterology 30, 373379.
Debets-Ossenkopp, YJ, Pot, RGJ, van Westerloo, DJ, Goddwin, A, Vandenbroucke-Grauls, CMJE, Berg, DE, Hoffman, PS and Kusters, JG (1999) Insertion of mini-IS605 and deletion of adjacent sequences in the nitroreductase (rdxA) gene cause metronidazole resistance in Helicobacter pylori NCTC11637. Antimicrobial Agents and Chemotherapy 43, 26572662.
Diniz, CG, Farias, LM, Carvalho, MAR, Rocha, ER and Smith, CJ (2004) Differential gene expression in a Bacteroides fragilis metronidazole-resistant mutant. Journal of Antimicrobial Chemotherapy 54, 100108.
Dobiás, L, Cerná, M, Rössner, P and Srám, R (1994) Genotoxicity and carcinogenicity of metronidazole. Mutation Research 317, 177194.
Dunn, LA, Burgess, AG, Krauer, KG, Eckmann, L, Vanelle, P, Crozet, MD, Gillin, FD, Upcroft, P and Upcroft, JA (2010) A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro. International Journal of Antimicrobial Agents 36, 3742.
Durel, P, Couture, J, Collart, P and Giro, C (1960) Flagyl (metronidazole). British Journal of Veneral Diseases 36, 154162.
Edwards, DI (1993) Nitroimidazole drugs – action and resistance mechanisms. I. Mechanisms of action. Journal of Antimicrobial Chemotherapy 31, 920.
Ellis, JE, Cole, D and Lloyd, D (1992) Influence of oxygen on the fermentative metabolism of metronidazole-sensitive and resistant strains of Trichomonas vaginalis. Molecular and Biochemical Parasitology 56, 7988.
Ellis, JE, Wingfield, JM, Cole, D, Boreham, PF and Lloyd, D (1993) Oxygen affinities of metronidazole-resistant and -sensitive stocks of Giardia intestinalis. International Journal for Parasitolology 23, 3539.
Falagas, ME, Walker, AM, Jick, H, Ruthazer, R, Griffith, J and Snydman, DR (1998) Late incidence of cancer after metronidazole use: a matched metronidazole user/nonuser study. Clinical and Infectious Diseases 26, 384388.
Freeman, WA, McFadzean, JA and Whelan, JP (1968) Activity of metronidazole against experimental tetanus and gas gangrene. Journal of Applied Bacteriology 31, 443447.
Friedman, GD, Jiang, SF, Udaltsova, N, Quesenberry, CP Jr., Cha, J and Habel, LA (2009) Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicity. International Journal of Cancer 125, 21732178.
Fung, HB and Doan, TL (2005) Tinidazole: a nitroimidazole antiprotozoal agent. Clinical Therapy 27, 18591884.
Füzi, M and Csukás, Z (1969a) A yet unknown antibacterial effect of metronidazole. Orvosi Hetilap 110, 16051606.
Füzi, M and Csukás, Z (1969b) Sensitivity of microorganisms of the oral flora to metronidazole. Orvosi Hetilap 110, 21542155.
Gal, M and Brazier, JD (2004) Metronidazole resistance in Bacteroides spp. carrying nim genes and the selection of slow-growing metronidazole-resistant mutants. Journal of Antimicrobial Chemotherapy 54, 109116.
Gerrits, MM, van der Wouden, EJ, Bax, DA, van Zwet, AA, van Vliet, AH, de Jong, A, Kusters, JG, Thijs, JC and Kuipers, EJ (2004) Role of the rdxA and frxA genes in oxygen-dependent metronidazole resistance of Helicobacter pylori. Journal of Medical Microbiology 53, 11231128.
Gillin, FD and Reiner, DS (1982) Effects of oxygen tension and reducing agents on sensitivity of Giardia lamblia to metronidazole in vitro. Biochemical Pharmacology 31, 36943697.
Goodwin, A, Kersulyte, D, Sisson, G, Veldhuyzen van Zanten, SOJ, Berg, DE and Hoffman, PS (1998) Metronidazole resistance in Helicobacter pylori is due to null mutations in a gene (rdxA) that encodes an oxygen-insensitive NADPH nitroreductase. Molecular Microbiology 28, 383393.
Gookin, JL, Hanrahan, K and Levy, MG (2017) The conundrum of feline trichomonosis. Journal of Feline Medical Surgery 19, 261274.
Haggoud, A, Reysset, G, Azeddoug, H and Sebald, M (1994) Nucleotide sequence analysis of two 5-nitroimidazole resistance determinants from Bacteroides strains and of a new insertion sequence upstream of the two genes. Antimicrobial Agents and Chemotherapy 38, 10471051.
Hedberg, M and Nord, CE (2003) Antimicrobial susceptibility of Bacteroides fragilis group isolates in Europe. Clinical Microbiology and Infection 9, 475488.
Hirschl, AM, Hentschel, E, Schütze, K, Nemec, H, Pötzi, R, Gangl, A, Weiss, W, Pletschette, M, Stanek, G and Rotter, ML (1988) The efficacy of antimicrobial treatment in Campylobacter pylori-associated gastritis and duodenal ulcer. Scandinavian Journal of Gastroenterology Supplement 142, 7681.
Holmes, AH, Moore, LS, Sundsfjord, A, Steinbakk, M, Regmi, S, Karkey, A, Guerin, PJ and Piddock, LJ (2016) Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 387, 176187.
Hrdy, I, Cammack, R, Stopka, P, Kulda, J and Tachezy, J (2005) Alternative pathway of metronidazole activation in Trichomonas vaginalis hydrogenosomes. Antimicrobial Agents and Chemotherapy 49, 50335036.
Husain, F, Veeranagouda, Y, His, J, Meggersee, R, Abratt, V and Wexler, HM (2013) Two multidrug-resistant clinical isolates of Bacteroides fragilis carry a novel metronidazole resistance nim gene (nimJ). Antimicrobial Agents and Chemotherapy 57, 37673774.
Ings, RMJ, McFadzean, JA and Ormerod, WE (1974) The mode of action of metronidazole in Trichomonas vaginalis and other micro-organisms. Biochemical Pharmacology 23, 14211429.
Jarrad, AM, Debnath, A, Miyamoto, Y, Hansford, KA, Pelingon, R, Butler, MS, Bains, T, Karoli, T, Blaskovich, MA, Eckmann, L and Cooper, MA (2016) Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis. European Journal of Medicinal Chemistry 120, 353362.
Jeelani, G, Husain, A, Sato, D, Ali, V, Suematsu, M, Soga, T and Nozaki, T (2010) Two atypical L-cysteine-regulated NADPH-dependent oxidoreductases involved in redox maintenance, L-cystine and iron reduction, and metronidazole activation in the enteric protozoan Entamoeba histolytica. Journal of Biological Chemistry 285, 2688926899.
Jenks, PJ, Ferrero, RL and Labigne, A (1999a) The role of the rdxA gene in the evolution of metronidazole resistance in Helicobacter pylori. Journal of Antimicrobial Chemotherapy 43, 753758.
Jenks, PJ, Labigne, A and Ferrero, RL (1999b) Exposure to metronidazole in vivo readily induces resistance in Helicobacter pylori and reduces the efficacy of eradication therapy in mice. Antimicrobial Agents and Chemotherapy 43, 777781.
Jennings, FW and Urquhart, GM (1983) The use of the 2 substituted 5-nitroimidazole, fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice. Zeitschrift für Parasitenkunde 69, 577581.
Justino, MC, Parente, MR, Boneca, IG and Saraiva, LM (2014) Frxa is an S-nitrosoglutathione reductase enzyme that contributes to Helicobacter pylori pathogenicity. The FEBS Journal 281, 44954505.
Kaakoush, NO, Asencio, C, Mégraud, F and Mendz, GL (2009) A redox basis for metronidazole resistance in Helicobacter pylori. Antimicrobial Agents and Chemotherapy 53, 18841891.
Kedderis, GL, Argenbright, LS and Miwa, GT (1988) Mechanism of reductive activation of 5-nitroimidazole by flavoproteins: model studies with dithionite. Archives of Biochemistry and Biophysics 262, 4048.
Korting, HC and Schöllmann, C (2009) Current topical and systemic approaches to treatment of rosacea. Journal of the European Academy of Dermatology and Venerology 23, 876882.
Koss, CA, Baras, DC, Lane, SD, Aubry, R, Marcus, M, Markowitz, LE and Koumans, EH (2012) Investigation of metronidazole use during pregnancy and adverse birth outcomes. Antimicrobial Agents and Chemotherapy 56, 48004805.
Kulda, J (1999) Trichomonads, hydrogenosomes and drug resistance. International Journal for Parasitology 29, 199212.
Kulda, J, Tachezy, J and Cerkasovová, A (1993) In vitro induced anaerobic resistance to metronidazole in Trichomonas vaginalis. Journal of Eukaryotic Microbiology 40, 262269.
Kwon, DH, Kato, M, El-Zaatari, FAK, Osato, MS and Graham, DY (2000) Frame-shift mutations in NAD(P)H flavin oxidoreductase encoding gene (frxA) from metronidazole resistant Helicobacter pylori ATCC43504 and its involvement in metronidazole resistance. FEMS Microbiology Letters 188, 197202.
Kwon, DH, Hulten, K, Kato, M, Kim, JJ, Lee, M, El-Zaatari, FA, Osato, MS and Graham, DY (2001) DNA sequence analysis of rdxA and frxA from 12 pairs of metronidazole-sensitive and -resistant clinical Helicobacter pylori isolates. Antimicrobial Agents and Chemotherapy 45, 26092615.
Land, KM, Delgadillo-Correa, MG, Tachezy, J, Vanacova, S, Hsieh, CL, Sutak, R and Johnson, PJ (2004) Targeted gene replacement of a ferredoxin gene in Trichomonas vaginalis does not lead to metronidazole resistance. Molecular Microbiology 51, 115122.
LaRusso, NA, Tomasz, M, Kaplan, D and Müller, M (1978) Interaction of metronidazole with nucleic acids in vitro. Antimicrobial Agents and Chemotherapy 13, 1924.
Latham, SR, Labigne, A and Jenks, PJ (2002) Production of the RdxA protein in metronidazole-susceptible and -resistant isolates of Helicobacter pylori cultured from treated mice. Journal of Antimicrobial Chemotherapy 49, 675678.
Leffler, DA and Lamont, JT (2015) Clostridium difficile infection. New England Journal of Medicine 373, 287288.
Leitsch, D, Kolarich, D, Wilson, IBH, Altmann, F and Duchêne, M (2007) Nitroimidazole action in Entamoeba histolytica: a central role for thioredoxin reductase. PLoS Biology 5, 18201834.
Leitsch, D, Kolarich, D, Binder, M, Stadlmann, J, Altmann, F and Duchêne, M (2009) Trichomonas vaginalis: metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system. Implications for nitroimidazole toxicity and resistance. Molecular Microbiology 72, 518536.
Leitsch, D, Kolarich, D and Duchêne, M (2010) The flavin inhibitor diphenyleneiodonium renders Trichomonas vaginalis resistant to metronidazole, inhibits thioredoxin reductase and flavin reductase, and shuts off hydrogenosomal enzymatic pathways. Molecular and Biochemical Parasitology 171, 1724.
Leitsch, D, Burgess, AG, Dunn, LA, Krauer, KG, Tan, K, Duchêne, M, Upcroft, P, Eckmann, L and Upcroft, JA (2011) Pyruvate:ferredoxin oxidoreductase and thioredoxin reductase are involved in 5-nitroimidazole activation while flavin metabolism is linked to 5-nitroimidazole resistance in Giardia lamblia. Journal of Antimicrobial Chemotherapy 66, 17561766.
Leitsch, D, Drinić, M and Duchêne, M (2012a) Down-regulation of flavin reductase and alcohol dehydrogenase-1 (ADH-1) in metronidazole-resistant isolates of Trichomonas vaginalis. Molecular and Biochemical Parasitology 183, 177183.
Leitsch, D, Schlosser, S, Burgess, A and Duchêne, M (2012b) Nitroimidazole drugs vary in their mode of action in the human parasite Giardia lamblia. International Journal for Parasitology: Drugs and Drug Resistance 2, 166170.
Leitsch, D, Williams, CF, Lloyd, D and Duchêne, M (2013) Unexpected properties of NADP-dependent secondary alcohol dehydrogenase (ADH-1) in Trichomonas vaginalis and other microaerophilic parasites. Experimental Parasitology 134, 374380.
Leitsch, D, Janssen, BD, Kolarich, D, Johnson, PJ and Duchêne, M (2014a) Trichomonas vaginalis flavin reductase 1 and its role in metronidazole resistance. Molecular Microbiology 91, 198208.
Leitsch, D, Sóki, J, Kolarich, D, Urbán, E and Nagy, E (2014b) A study on Nim expression in Bacteroides fragilis. Microbiology 160, 616622.
Leitsch, D, Müller, J and Müller, N (2016) Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target. International Journal for Parasitology: Drugs and Drug Resistance 6, 148153.
Lemée, V, Zaharia, I, Nevez, G, Rabodonirina, M, Brasseur, P, Ballet, JJ and Favennec, L (2000) Metronidazole and albendazole susceptibility of 11 clinical isolates of Giardia duodenalis from France. The Journal of Antimicrobial Chemotherapy 46, 819821.
Lindmark, DG and Müller, M (1976) Antitrichomonad action, mutagenicity, and reduction of metronidazole and other nitroimidazoles. Antimicrobial Agents and Chemotherapy 10, 476482.
Linstead, DJ and Bradley, S (1988) The purification and properties of two soluble reduced nicotinamide:acceptor oxidoreductases from Trichomonas vaginalis. Molecular and Biochemical Parasitology 27, 125133.
Lloyd, D and Pedersen, JZ (1985) Metronidazole radical anion generation in vivo in Trichomonas vaginalis: oxygen quenching is enhanced in a drug-resistant strain. Journal of General Microbiology 131, 8792.
Löfmark, S, Fang, H, Hedberg, M and Edlund, C (2005) Inducible metronidazole resistance and nim genes in clinical Bacteroides fragilis group isolates. Antimicrobial Agents and Chemotherapy 49, 12531256.
Lozniewski, A, Labia, R, Haristoy, X and Mory, F (2001) Antimicrobial susceptibilities of clinical Desulfovibrio isolates. Antimicrobial Agents and Chemotherapy 45, 29332935.
Ludlum, D, Colinas, RJ, Kirk, MC and Mehta, JR (1988) Reaction of reduced metronidazole with guanosine to form an unstable adduct. Carcinogenesis 9, 593596.
Maeda, K, Osato, T and Umezawa, H (1953) A new antibiotic, azomycin. Journal of Antibiotics 6, 182.
Marais, A, Bilardi, C, Cantet, F, Mendz, GL and Mégraud, F (2003) Characterization of the genes rdxA and frxA involved in metronidazole resistance in Helicobacter pylori. Research in Microbiology 154, 137144.
Mason, RP and Holtzman, JL (1975) The role of catalytic superoxide formation in the O2 inhibition of nitroreductase. Biochemical and Biophysical Research Communications 67, 12671274.
Mastronicola, D, Giuffrè, A, Testa, F, Mura, A, Forte, E, Bordi, E, Pucillo, LP, Fiori, PL and Sarti, P (2011) Giardia intestinalis escapes oxidative stress by colonizing the small intestine: a molecular hypothesis. IUBMB Life 63, 2125.
Meingassner, JG and Thurner, J (1979) Strain of Trichomonas vaginalis resistant to metronidazole and other 5-nitroimidazoles. Antimicrobial Agents and Chemotherapy 15, 254257.
Meingassner, JG, Mieth, H, Czok, R, Lindmark, DG and Müller, M (1978) Assay conditions and the demonstration of nitroimidazole resistance in Tritrichomonas foetus. Antimicrobial Agents and Chemotherapy 13, 13.
Moreno, SN, Mason, RP, Muniz, RP, Cruz, FS and Docampo, R (1983) Generation of free radicals from metronidazole and other nitroimidazoles by Tritrichomonas foetus. Journal of Biological Chemistry 258, 40514054.
Moreno, SNJ, Mason, RP and Docampo, R (1984) Distinct reduction of nitrofurans and metronidazole to free radical metabolites by Tritrichomonas foetus hydrogenosomal and cytosolic enzymes. Journal of Biological Chemistry 259, 82528259.
Mørch, K, Hanevik, K, Robertson, LJ, Strand, EA and Langeland, N (2008) Treatment-ladder and genetic characterisation of parasites in refractory giardiasis after an outbreak in Norway. Journal of Infect Diseases 56, 268273.
Müller, M and Gorrell, TE (1983) Metabolism and metronidazole uptake in Trichomonas vaginalis isolates with different metronidazole susceptibilities. Antimicrobial Agents and Chemotherapy 24, 667673.
Müller, M, Lossick, J and Gorrell, T (1988) In vitro susceptibility of Trichomonas vaginalis to metronidazole and treatment outcome in vaginal trichomoniasis. Sexually Transmitted Diseases 15, 1724.
Müller, J, Wastling, J, Sanderson, S, Müller, N and Hemphill, A (2007) A novel Giardia lamblia nitroreductase, GlNR1, interacts with nitazoxanide and other thiazolides. Antimicrobial Agents and Chemotherapy 51, 19791986.
Müller, J, Schildknecht, P and Müller, N (2013) Metabolism of nitro drugs metronidazole and nitazoxanide in Giardia lamblia: characterization of a novel nitroreductase (GlNR2). Journal of Antimicrobial Chemotherapy 68, 17811789.
Müller, J, Rout, S, Leitsch, D, Vaithilingam, J, Hehl, A and Müller, N (2015) Comparative characterization of two nitroreductases from Giardia lamblia as potential activators of nitro compounds. International Journal for Parasitology: Drugs and Drug Resistance 5, 3743.
Nagy, E and Földes, J (1991) Inactivation of metronidazole by Enterococcus faecalis. Journal of Antimicrobial Chemotherapy 27, 6770.
Nailor, MD and Sobel, JD (2007) Tinidazole for the treatment of vaginal infections. Expert Opinion on Investigational Drugs 16, 743751.
Narikawa, S (1986) Distribution of metronidazole susceptibility factors in obligate anaerobes. Journal of Antimicrobial Chemotherapy 18, 565574.
Nash, TE (2001) Treatment of Giardia lamblia infections. The Pediatric Infectious Disease Journal 20, 193195.
Nastro, LJ and Finegold, SM (1972) Bactericidal activity of five antimicrobial agents against Bacteroides fragilis. Journal of Infectious Diseases 126, 104107.
Nicol, CS, Barrow, J and Redmond, A (1960) Flagyl (8823 RP) in the treatment of trichomoniasis. British Journal of Venereal Diseases 36, 152153.
Nillius, D, Müller, J and Müller, N (2011) Nitroreductase (GlNR1) increases susceptibility of Giardia lamblia and Escherichia coli to nitro drugs. Journal of Antimicrobial Chemotherapy 66, 10291035.
Olekhnovich, IN, Goodwin, A and Hoffman, PS (2009) Characterization of the NAD(P)H oxidase and metronidazole reductase activities of the RdxA nitroreductase of Helicobacter pylori. The FEBS Journal 276, 33543364.
Pal, D, Banerjee, S, Cui, J, Schwartz, A, Ghosh, SK and Samuelson, J (2009) Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrobial Agents and Chemotherapy 53, 458464.
Paulish-Miller, TE, Augostini, P, Schuyler, JA, Smith, WL, Mordechai, E, Adelson, ME, Gygax, SE, Secor, WE and Hilbert, DW (2014) Trichomonas vaginalis metronidazole resistance is associated with single nucleotide polymorphisms in the nitroreductase genes ntr4Tv and ntr6Tv. Antimicrobial Agents and Chemotherapy 58, 29382943.
Peng, Z, Jin, D, Kim, HB, Stratton, CW, Wu, B, Tang, YW and Sun, X (2017) Update on antimicrobial resistance in Clostridium difficile: resistance mechanisms and antimicrobial susceptibility testing. Journal of Clinical Microbiology 55, 19982008.
Penuliar, GM, Nakada-Tsukui, K and Nozaki, T (2015) Phenotypic and transcriptional profiling in Entamoeba histolytica reveal costs to fitness and adaptive responses associated with metronidazole resistance. Frontiers in Microbiology 6, 354.
Pervez-Reyes, E, Kalyanaraman, B and Mason, RP (1980) The reductive metabolism of metronidazole and ronidazole by aerobic liver microsomes. Molecular Pharmacology 17, 239244.
Plant, CW and Edwards, DI (1976) Effect of tinidazole, metronidazole and nitrofurazone on nucleic acid synthesis in Clostridium bifermentans. Journal of Antimicrobial Chemotherapy 2, 203209.
Powell, SJ, MacLeod, I, Wilmot, AJ and Elsdon-Dew, R (1966) Metronidazole in amoebic dysentery and amoebic liver abscess. Lancet 2, 13291331.
Pumbwe, L, Glass, D and Wexler, HM (2006) Efflux pump overexpression in multiple-antibiotic-resistant mutants of Bacteroides fragilis. Antimicrobial Agents and Chemotherapy 50, 31503153.
Pumbwe, L, Chang, A, Smith, RL and Wexler, HM (2007) BmeRABC5 is a multidrug efflux system that can confer metronidazole resistance in Bacteroides fragilis. Microbial Drug Resistance 13, 96101.
Raether, W and Seidenath, H (1983) The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Annals of Tropical Medicine and Parasitology 77, 1326.
Ralph, ED, Clarke, JT, Libke, RD, Luthy, RP and Kirby, WM (1974) Pharmacokinetics of metronidazole as determined by bioassay. Antimicrobial Agents and Chemotherapy 6, 691696.
Ralph, ED, Austin, TW, Pattison, FL and Schieven, BC (1979) Inhibition of Haemophilus vaginalis (Corynebacterium vaginale) by metronidazole, tetracycline, and ampicillin. Sexually Transmitted Diseases 6, 199202.
Rasoloson, D, Vanacova, S, Tomkova, E, Razga, J, Hrdy, I, Tachezy, J and Kulda, J (2002) Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalis. Microbiology 48, 24672477.
Ribardo, DA, Bingham-Ramos, LK and Hendrixson, DR (2010) Functional analysis of the RdxA and RdxB nitroreductases of Campylobacter jejuni reveals that mutations in rdxA confer metronidazole resistance. Journal of Bacteriology 192, 18901901.
Rodin, P, King, AJ, Nicol, CS and Barrow, J (1960) Flagyl in the treatment of trichomoniasis. British Journal of Venereal Diseases 36, 147151.
Samarawickrema, NA, Brown, DM, Upcroft, JA, Thammapalerd, N and Upcroft, P (1997) Involvement of superoxide dismutase and pyruvate:ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica. Journal of Antimicrobial Chemotherapy 40, 833840.
Sánchez, LB, Elmendorf, H, Nash, TE and Müller, M (2001) NAD(p)H:menadione oxidoreductase of the amitochondriate eukaryote Giardia lamblia: a simpler homologue of the vertebrate enzyme. Microbiology 147, 561570.
Schaumann, R, Petzold, S and Rodloff, AC (2005) Inducible metronidazole resistance in nim-positive and nim-negative Bacteroides fragilis group strains after several passages on metronidazole containing Columbia agar plates. Infection 33, 368372.
Schneider, J (1961) Treatment of giardiasis (lambliasis) by metronidazole. Bulletin de la Société de Pathologie Exotique 54, 8495.
Schwebke, JR and Barrientes, FJ (2006) Prevalence of Trichomonas vaginalis isolates with resistance to metronidazole and tinidazole. Antimicrobial Agents and Chemotherapy 50, 42094210.
Sebald, M (1994) Genetic basis for antibiotic resistance in anaerobes. Clinical Infectious Dieases 18(Suppl 4), S297-S304.
Semer, JM, Friedland, P, Vaisberg, M and Greenberg, A (1966) The use of metronidazole in the treatment of alcoholism: a pilot study. American Journal of Psychiatry 123, 722724.
Sheikh, SO, Jabeen, K, Qaiser, S, Ahsan, ST, Khan, E and Zafar, A (2015) High rate of non-susceptibility to metronidazole and clindamycin in anaerobic isolates: data from a clinical laboratory from Karachi, Pakistan. Anaerobe 33, 132136.
Sindar, P, Britz, ML and Wilkinson, RG (1982) Isolation and properties of metronidazole-resistant mutants of Clostridium perfringens. Journal of Medical Microbiology 15, 503509.
Smith, MA and Edwards, DI (1995) Redox potential and oxygen concentration as factors in the susceptibility of Helicobacter pylori to nitroheterocyclic drugs. Journal of Antimicrobial Chemotherapy 35, 751764.
Smith, PD, Gillin, FD, Spira, WM and Nash, TE (1982) Chronic giardiasis: studies on drug sensitivity, toxin production, and host immune response. Gastroenterology 83, 797803.
Snydman, DR, Jacobus, NV, McDermott, LA, Goldstein, EJ, Harrell, L, Jenkins, SG, Newton, D, Patel, R and Hecht, DW (2017) Trends in antimicrobial resistance among Bacteroides species and Parabacteroides species in the United States from 2010–2012 with comparison to 2008–2009. Anaerobe 43, 2126.
Sobel, JD, Nyiresy, P and Brown, W (2001) Tinidazole therapy for metronidazole-resistant vaginal trichomonosis. Clinical Infectious Diseases 33, 13411346.
Sóki, J, Gal, M, Brazier, JS, Rotimi, VO, Urbán, E, Nagy, E and Duerden, BI (2006) Molecular investigation of genetic elements contributing to metronidazole resistance in Bacteroides strains. Journal of Antimicrobial Chemotherapy 57, 212220.
Sóki, J, Eitel, Z, Urbán, E, Nagy, E and ESCMID Study Group on Anaerobic Infections (2013) Molecular analysis of the carbapenem and metronidazole resistance mechanisms of Bacteroides strains reported in a Europe-wide antibiotic resistance survey. International Journal of Antimicrobial Agents 41, 122125.
Sutak, R, Dolezal, P, Fiumera, HL, Hrdy, I, Dancis, A, Delgadillo-Correa, M, Johnson, PJ, Müller, M and Tachezy, J (2004) Mitochondrial-type assembly of FeS centers in the hydrogenosomes of the amitochondriate eukaryote Trichomonas vaginalis. Proceedings of the National Academy of Sciences of the United States of America 101, 1036810373.
Tachezy, J, Kulda, J and Tomková, E (1993) Aerobic resistance of Trichomonas vaginalis to metronidazole induced in vitro. Parasitology 106, 3137.
Tejman-Yarden, N, Millman, M, Lauwaet, T, Davids, BJ, Gillin, FD, Dunn, L, Upcroft, JA, Miyamoto, Y and Eckmann, L (2011) Impaired parasite attachment as fitness cost of metronidazole resistance in Giardia lamblia. Antimicrobial Agents and Chemotherapy 55, 46434651.
Townson, SM, Laqua, H, Upcroft, P, Boreham, PF and Upcroft, JA (1992) Induction of metronidazole and furazolidone resistance in Giardia. Transactions of the Royal Society of Tropical Medicine and Hygene 86, 521522.
Trend, MA, Jorgensen, MA, Hazell, SL and Mendz, GL (2001) Oxidases and reductases are involved in metronidazole sensitivity in Helicobacter pylori. International Journal of Biochemistry and Cell Biology 33, 143153.
Upcroft, P and Upcroft, JA (2001) Drug targets and mechanisms of resistance in the anaerobic protozoa. Clinical Microbiology Reviews 14, 150164.
Upcroft, JA, Dunn, L, Wal, T, Tabrizi, S, Delgadillo-Correa, MG, Johnson, PJ, Garland, S, Siba, P and Upcroft, P (2009) Metronidazole resistance in Trichomonas vaginalis from highland women in Papua New Guinea. Sexual Health 6, 334338.
Urbán, E, Sóki, J, Brazier, JS, Nagy, E and Duerden, BI (2002) Prevalence and characterization of nim genes of Bacteroides spp. isolated in Hungary. Anaerobe 8, 175179.
Uzlikova, M and Nohynkova, E (2014) The effect of metronidazole on the cell cycle and DNA in metronidazole-susceptible and -resistant Giardia cell lines. Molecular and Biochemical Parasitology 198, 7581.
Veeranagouda, Y, Husain, F, Boente, R, Moore, J, Smith, CJ, Rocha, ER, Patrick, S and Wexler, HM (2014) Deficiency of the ferrous iron transporter FeoAB is linked with metronidazole resistance in Bacteroides fragilis. Journal of Antimicrobial Chemotherapy 69, 26342643.
Vieira, JMBD, Boente, RF, Miranda, KR, Avelar, KES, Domingues, RMCP and Ferreira, MC (2006) Decreased susceptibility to nitroimidazoles among Bacteroides species in Brazil. Current Microbiology 52, 2732.
Voogd, CE (1981) On the mutagenicity of nitroimidazoles. Mutation Research 186, 243277.
Voolmann, T and Boreham, P (1993) Metronidazole resistant Trichomonas vaginalis in Brisbane. Medical Journal of Australia 159, 490.
Wardman, P (1985) Some reactions and properties of nitro radical-anions important in biology and medicine. Environmental Health Perspectives 64, 309320.
Wassmann, C, Hellberg, A, Tannich, E and Bruchhaus, I (1999) Metronidazole resistance in the protozoan parasite Entamoeba histolytica is associated with increased expression of iron-containing superoxide dismutase and peroxiredoxin and decreased expression of ferredoxin 1 and flavin reductase. Journal of Biological Chemistry 274, 2605126056.
Wendel, KA and Workowski, KA (2007) Trichomoniasis: challenges to appropriate management. Clinical Infectious Diseases 44(Suppl 3), 123129.
Williams, CF, Lloyd, D, Kolarich, D, Alagesan, K, Duchêne, M, Cable, J, Williams, D and Leitsch, D (2012) Disrupted intracellular redox balance of the diplomonad fish parasite Spironucleus vortens by 5-nitroimidazoles and garlic-derived compounds. Veterinary Parasitology 190, 6273.
Willson, RL and Searle, AJ (1975) Metronidazole (Flagyl): iron catalysed reaction with sulphydryl groups and tumour radiosensitisation. Nature 255, 498500.
Wislocki, PG, Bagan, ES, Vandenheuvel, WJA, Walker, RW, Alvaro, RF, Arison, BH, Lu, AYH and Wolf, FJ (1984) Drug residue formation from ronidazole, a 5-nitroimidazole. V. Cysteine adducts formed upon reduction of ronidazole by dithionite or rat liver enzymes in the presence of cysteine. Chemical-Biological Interactions 49, 1325.
Wood, BA and Monro, AM (1975) Pharmacokinetics of tinidazole and metronidazole in women after single large oral doses. British Journal of Venereal Diseases 51, 5153.
Yarlett, N, Yarlett, NC and Lloyd, D (1986) Metronidazole-resistant clinical isolates of Trichomonas vaginalis have lowered oxygen affinities. Molecular and Biochemical Parasitology 19, 111116.
Yehya, M, Hamze, M, Mallat, H and Dabbousi, F (2014) Prevalence and antibiotic susceptibility of Bacteroides fragilis group isolated from stool samples in North Lebanon. Brazilian Journal of Microbiology 44, 807812.
Zahoor, A, Lafleur, MVM, Knight, RC, Loman, H and Edwards, DI (1987) DNA damage induced by reduced nitroimidazole drugs. Biochemical Pharmacology 36, 32993304.
Zaman, V and Natarajan, PN (1969) In vitro trials of metronidazole against Balantidium coli. Transactions of the Royal Society of Tropical Medicine and Hygiene 63, 152.



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