Metronidazole
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Metronidazole resistance in the B. fragilis group is often associated with the presence of nim genes (Haggoud et al., 1994; Reysset, 1996; Stubbs et al., 2000; Lofmark et al., 2005; B D Vieira et al., 2006; Sherwood et al., 2011; Hartmeyer et al., 2012; Brook et al., 2013; Urban et al., 2015; Sadarangani et al., 2015). There are up to nine variants, including; nimA-H and nimJ (Husain et al., 2013). These nim genes may be present in the bacterial cell chromosome or mobile plasmids or conjugative transposons (Husain et al., 2014). The nim gene appears to encode a nitroimidazole reductase, which serves to reduce metronidazole to amine derivatives instead of toxic nitroso residues that are required for antimicrobial activity (Carlier et al., 1997). However, the presence of nim does not necessarily confer phenotypic resistance to metronidazole (Stubbs et al., 2000; Haggoud et al., 2001; Gal and Brazier, 2004; Soki et al., 2013). Expression of nim appears to require the presence of an insertion sequence located upstream of nim (Haggoud et al., 1994). However, a recent study found no correlation between nim levels and levels of metronidazole resistance (Leitsch et al., 2014b).
Entamoeba histolytica
Dongyou Liu in Handbook of Foodborne Diseases, 2018
Today, dysentery IA is treated with nitroimidazoles (metronidazole or tinidazole), the drug of choice for the treatment of symptomatic and invasive disease.131,132 Metronidazole kills amoebae in the intestine and in tissues, but it does not eradicate intestinal cysts.133 Metronidazole appears to be absorbed into amoebae, producing nitroso intermediates that bind to DNA and enzymes such as thioredoxin reductase forming adducts; antimicrobial effects may result due to the production of free radicals.134 As parasites persist in the intestines of 40%–60% of patients treated with metronidazole, drugs such as paromomycin, diloxanide furoate, or iodoquinol are used to eradicate residual amoebae.135,136 Diloxanide furoate is used alone as a primary agent to treat asymptomatic E. histolytica cyst passers.137 Paromomycin is the drug of choice for treating noninvasive disease.133 Iodoquinol primarily acts in the bowel lumen because it is poorly absorbed.133 Nitroimidazoles with long half-lives (i.e., secnidazole and ornidazole) are also used. Nitroimidazole therapy leads to a clinical response in roughly 90% of patients with mild to moderate IA.131 Nitazoxanide and its active-circulating metabolite tizoxanide are as potent as metronidazole against metronidazole-sensitive isolates of E. histolytica in vitro and have activity against isolates resistant or poorly susceptible to metronidazole.137 Nitazoxanide is effective at treating invasive IA and at preventing the amoebic colonization of the GI tract.138
Metronidazole in the Elderly
Thomas T. Yoshikawa, Shobita Rajagopalan in Antibiotic Therapy for Geriatric Patients, 2005
The nitroimidazole compounds include metronidazole and the related compounds tinidazole and nimorazole. Metronidazole is a small, uncharged molecule whose antimicrobial effect requires activation by bacterial or parasitic enzymes. The chain of events required for drug activity include: (1) uptake of the drug by the bacterial or parasitic cell, (2) reduction of the drug to an active metabolite, (3) interference with cellular elements (DNA, RNA, protein) by short-lived intermediate metabolites, and (4) cellular excretion of inactive end products. Metronidazole enters both aerobic and anaerobic bacteria; however, it has activity only in those organisms possessing anaerobic metabolic pathways able to metabolize it to active end products. This unique feature of the drug accounts for the fact that it has activity against both anaerobic bacteria as well as anaerobic eukaryotes such as Trichomonas vaginalis and Entamoeba histolytica. Following diffusion into the cell, the nitro side chain of metronidazole is quickly reduced by donation of electrons from ferredoxin-like electron transport proteins (1). This active reduction occurs only in strict anaerobic microorganisms and leads to the formation of short-lived but cytotoxic intermediates including nitroso-free radicals, nitroso- and hydroxylamine derivates. Metronidazole's subsequent mechanism of action is poorly understood; however, it is believed that these cytotoxic intermediates interfere with DNAs of target cells. Subsequent laboratory experiments have shown that reduced metronidazole metabolites interfere with DNA synthesis while unchanged drug does not. The reduced intermediates may attach directly to nucleic acids or cause single-stranded or double-stranded breaks in cellular DNA. Further metabolism of the cytotoxic intermediates of metronidazole leads to the production of acetamide and 2-hydroxyethyl oxamic acid as well as other equally inactive end products.
Design, synthesis, in vitro inhibition and toxicological evaluation of human carbonic anhydrases I, II and IX inhibitors in 5-nitroimidazole series
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ashok Aspatwar, Nanda Kumar Parvathaneni, Harlan Barker, Emilie Anduran, Claudiu T. Supuran, Ludwig Dubois, Philippe Lambin, Seppo Parkkila, Jean-Yves Winum
In addition, in this study, we were interested in incorporating a nitro-imidazole moiety as a privileged hypoxia sensitising scaffold in the structure of CA inhibitors. The rationale was to investigate a strategy of dual targeting (hypoxia and hCA IXn/hCA XII) in the context of anticancer agents17. Previous results have shown the validity of this approach when conjugation of 5-nitroimidazole derivatives to CA inhibitors structures led to new radiosensitiser agents targeting hypoxic tumours17–20. To further investigate the effect and the influence of the 5-nitro imidazole moiety and develop new potent and safer inhibitors, we have been continuing our research on new inhibitors in the nitroimidazole series. In the present study, we report the design, synthesis, in vitro CA inhibition, and evaluation of toxicity of novel thiourea derivatives 3 and 4 and a sulphonamide derivative 10 using zebrafish larvae.
Successes, failures, and future prospects of prodrugs and their clinical impact
Published in Expert Opinion on Drug Discovery, 2019
Anas Najjar, Rafik Karaman
Antimicrobials of the 5-nitroimidazole class are the first line choice in the treatment of protozoal and some bacterial infections. Metronidazole and tinidazoleare are prodrugs with a similar proposed mechanism of action: the parent compound diffuses into the target organism and is reduced to several intermediates which cause cytotoxicity. Tinidazole is commonly prescribed for giardiasis, bacterial vaginosis, and H. pylori. Metronidazole, though, undergoes heavy hepatic metabolism producing 5 metabolites. Hydroxy-metronidazole, is an active metabolite with 30–65% of the antimicrobial activity of metronidazole [62]. Secnidazole is a second generation 5-nitroimidazole commonly prescribed for bacterial vaginosis. It is oxidized hepatically to an active hydroxyethyl metabolite. Both parent compound and its metabolite are clinically significant [61,63]. The mechanism of action of both secnidazole and its active metabolite is similar to that of metronidazole.
Is there room for immunomodulators in ulcerative colitis?
Published in Expert Opinion on Biological Therapy, 2020
Tarun Chhibba, Christopher Ma
Approximately one-quarter of patients will experience an adverse event with thiopurine therapy, with some prospective, real-world studies demonstrating the cumulative overall incidence of over 40% [103]. The majority of these will occur within the first 3 months of therapy [104,105]. Nausea is the most common adverse event associated with azathioprine use and discontinuation. The precise mechanism of nausea is unclear although it has been hypothesized that nitroimidazole, a product of non-enzymatic metabolism of azathioprine to 6-MP, is culpable as many patients are able to tolerate 6-MP after experiencing azathioprine-related nausea [104,105]. In a meta-analysis including 455 azathioprine-intolerant IBD patients, Kennedy et al. demonstrated that over two-thirds were able to tolerate mercaptopurine [106]. Other hypersensitivity allergic-type reactions have also been reported with azathioprine, although true hypersensitivity (comprised of fever, myalgias, rash, and flu-like symptoms) is uncommon [105].
Related Knowledge Centers
- Functional Group
- Imidazole
- Metronidazole
- Nitric Acid
- Organic Compound
- Sulfuric Acid
- Tinidazole
- Nitro Compound
- Nimorazole
- Dimetridazole