A review on metronidazole: an old warhorse in antimicrobial chemotherapy

Leitsch, David

doi:10.1017/s0031182017002025

Cited by 105 publications

(99 citation statements)

References 154 publications

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“…This could be explained by the fact that metronidazole has a very low midpoint redox potential. Therefore, the nitroreductases need other cofactors or interaction partners such as free ferredoxins with a similarly low potential that are not present in the in vitro assay (Leitsch, ). A fusion construct of NR3 and the ferredoxin domain of NR2 at its N‐terminus (see Appendix for details) expressed in E. coli does not confer increased susceptibility to metronidazole or increased resistance to tetracycline as compared to the original NR3 (Appendix Figure ).…”

Section: Discussionmentioning

confidence: 99%

Nitroreductases of bacterial origin in Giardia lamblia: Potential role in detoxification of xenobiotics

Müller

2019

MicrobiologyOpen

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The anaerobic parasite Giardia lamblia, causative agent of persistent diarrhea, contains a family of nitroreductase genes most likely acquired by lateral transfer from anaerobic bacteria or archaebacteria. Two of these nitroreductases, containing a ferredoxin domain at their N‐terminus, NR1, and NR2, have been characterized previously. Here, we present the characterization of a third member of this family, NR3. In functional assays, recombinant NR1 and NR3 reduced quinones like menadione and the antibiotic tetracycline, and—to much lesser extents—the nitro compound dinitrotoluene. Conversely, recombinant NR2 had no activity on tetracycline. Escherichia coli expressing NR3 were less susceptible to tetracycline, but more susceptible to the nitro compound metronidazole under semi‐aerobic growth conditions. G. lamblia overexpressing NR1 and NR3, but not lines overexpressing NR2, are more susceptible to the nitro drug nitazoxanide. These findings suggest that NR3 is an active quinone reductase with a mode of action similar to NR1, but different from NR2. The biological function of this family of enzymes may reside in the use of xenobiotics as final electron acceptors. Thereby, these enzymes may provide at least two evolutionary advantages namely a higher potential to recycle NAD(P) as electron acceptors for the (fermentative) energy and intermediary metabolism, and the possibility to inactivate toxic xenobiotics produced by microorganisms living in concurrence inside the intestinal habitat.

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Section: Discussionmentioning

confidence: 99%

Nitroreductases of bacterial origin in Giardia lamblia: Potential role in detoxification of xenobiotics

Müller

2019

MicrobiologyOpen

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“…The treatment against giardiasis comprises nitro compounds such as metronidazole (MET), other 5-nitroimidazole compounds, or nitazoxanide (NTZ) [10,11]. Moreover, G. lamblia is susceptible to a variety of antibiotics because of its prokaryote-like transcription and translation machineries, as well as to albendazole [12].…”

Section: Introductionmentioning

confidence: 99%

Metabolomic Profiling of Wildtype and Transgenic Giardia lamblia Strains by 1H HR-MAS NMR Spectroscopy

et al. 2020

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Giardia lamblia, a causative agent of persistent diarrhea in humans, domestic animals, and cattle, is usually treated with nitro compounds. Consequently, enzymes involved in anaerobic nitro reduction have been investigated in detail as potential targets. Their role within the normal metabolic context is, however, not understood. Using 1H high-resolution magic angle spinning (HR-MAS) NMR spectroscopy, we analyzed the metabolomes of G. lamblia trophozoites overexpressing three nitroreductases (NR1–NR3) and thioredoxin reductase (TrxR), most likely a scavenger of reactive oxygen species, as suggested by the results published in this study. We compared the patterns to convenient controls and to the situation in the nitro drug resistant strain C4 where NR1 is downregulated. We identified 27 metabolites in G. lamblia trophozoites. Excluding metabolites of high variability among different wildtype populations, only trophozoites overexpressing NR1 presented a distinct pattern of nine metabolites, in particular arginine catabolites, differing from the respective controls. This pattern matched a differential pattern between wildtype and strain C4. This suggests that NR1 interferes with arginine and thus energy metabolism. The exact metabolic function of NR1 (and the other nitroreductases) remains to be elucidated.

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“… 52 Other studies have shown less consistent results, indicating a role for PFOR, NR2 and TrxR and Flavin Mononucleotide-dependent oxidoreductases in MTZ resistance. 53 Novel “omics” approaches, looking at both RNA and protein levels, have enabled studies on genes and gene products expression in isogenic MTZ-susceptible and MTZ-resistant laboratory lines. Several lines of evidence emphasize the broad and variable adaptive responses in resistant isotypes, including post-transcriptional and post-translational alterations.…”

Section: Introductionmentioning

confidence: 99%

Treatment-refractory giardiasis: challenges and solutions

Lalle

Hanevik

2018

IDR

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Giardia is the commonest parasitic diarrheal pathogen affecting humans and a frequent cause of waterborne/foodborne parasitic diseases worldwide. Prevalence of giardiasis is higher in children, living in poor, low hygiene settings in developing countries, and in travelers returning from highly endemic areas. The clinical picture of giardiasis is heterogeneous, with high variability in severity of clinical disease. It can become chronic or be followed by post-infectious sequelae. An alarming increase in cases refractory to the conventional treatment with nitroimidazoles (ie, metronidazole) has been reported in low prevalence settings, such as European Union countries, especially in patients returning from Asia. In view of its relevance, we aim in this review to recapitulate present clinical knowledge about Giardia, with a special focus on the challenge of treatment-refractory giardiasis. We propose a working definition of clinically drug-resistant giardiasis, summarize knowledge regarding resistance mechanisms, and discuss its clinical management according to research-based evidence and medical practice. Advances in development and identification of novel drugs and potential non-pharmacological alternatives are also reviewed with the overall aim to define knowledge gaps and suggest future directions for research.

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A review on metronidazole: an old warhorse in antimicrobial chemotherapy

Cited by 105 publications

References 154 publications

Nitroreductases of bacterial origin in Giardia lamblia: Potential role in detoxification of xenobiotics

Nitroreductases of bacterial origin in Giardia lamblia: Potential role in detoxification of xenobiotics

Metabolomic Profiling of Wildtype and Transgenic Giardia lamblia Strains by 1H HR-MAS NMR Spectroscopy

Treatment-refractory giardiasis: challenges and solutions

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