Unexpected properties of NADP-dependent secondary alcohol dehydrogenase (ADH-1) in Trichomonas vaginalis and other microaerophilic parasites

Leitsch, David; Williams, Catrin H.; Lloyd, David; Duchêne, Michael

doi:10.1016/j.exppara.2013.03.034

Cited by 8 publications

(3 citation statements)

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“…In addition, and to make things even more complicated, different alterations might lead to the same phenotype. For example, metronidazole resistance is also strongly correlated with a decreased activity of alcohol dehydrogenase 1 (ADH1), a zincdependent enzyme that oxidizes secondary alcohols and reduces ketones (Leitsch et al 2012a(Leitsch et al , 2013. In some resistant strains ADH1 expression levels are downregulated, but in others, the decrease of ADH1 activity is caused by low intracellular zinc concentrations (Leitsch et al 2012a).…”

Section: Metronidazole Resistancementioning

confidence: 99%

A review on metronidazole: an old warhorse in antimicrobial chemotherapy

2017

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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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Section: Metronidazole Resistancementioning

confidence: 99%

A review on metronidazole: an old warhorse in antimicrobial chemotherapy

2017

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“…Considering the T. vaginalis gene expression data on their own, we found significant changes in expression of genes in carbohydrate metabolism, hydrogenosome function, and oxygen detoxification pathways. Major carbohydrate pathway genes, which have previously been implicated in Mz resistance [24,25,30,39,40] to be among the most differentially regulated in our RNA-Seq study (p < 0.05; Additional file 6; Additional file 1, Figure S3). Many genes coding for early stage glycolysis enzymes malate dehydrogenase gene TVAG_495880, and malic enzyme genes TVAG_416100 and TVAG_412220).…”

Section: Mz Resistance Is Associated With Regulation Of Genes Involvementioning

confidence: 89%

Genetic indicators of drug resistance in the highly repetitive genomes ofTrichomonas vaginalisand other trichomonads

Bradić

Warring

Tooley

et al. 2016

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BackgroundTrichomonas vaginalis, the most common non-viral sexually transmitted parasite, causes ~283 million trichomoniasis infections annually and is associated with complications during pregnancy and increased risk of HIV-1 acquisition. The antimicrobial drug metronidazole is used for treatment, but has lead to widespread drug resistance. We undertook sequencing of multiple clinical isolates and lab derived lines to identify genetic markers and mechanisms of metronidazole resistance. ResultsReduced representation genome sequencings of more than 100 T. vaginalis clinical isolates identified 3,923 SNP markers and presence of a bipartite population structure. Linkage disequilibrium decays rapidly, suggesting genome-wide recombination and the feasibility of genetic association studies in the parasite. We identified 72 SNPs associated with metronidazole resistance, and a comparison of SNPs within several lab-derived resistant lines revealed an overlap with the clinically resistant isolates. We identified SNPs in sets of genes for which no function has yet been assigned, as well as in functionallycharacterized genes highly relevant to drug resistance (e.g., pyruvate:ferredoxin oxidoreductase (PFO)).Transcription profiling of these and other genes served as proxy for testing the functional consequences of multiple identified SNPs. Transcription profiles of lab-derived drug resistance strain as well as clinically resistant strain depict common regulation changes in carbohydrate metabolism and oxygen detoxification pathways correlated with Mz resistance. Finally, we identified convergent genetic changes in lab-derived resistant lines of Tritrichomonas foetus, a distantly-related species that causes venereal disease in cattle. ConclusionsOur observation of shared genetic changes within and between T. vaginalis and Tr. foetus parasites suggests conservation of the pathways through which adaptation has occurred. These findings extend our knowledge of drug resistance in the parasite, providing a panel of markers that can be used as a diagnostic tool.

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“…Anaerobic resistance is characterized by decreased expression of genes/proteins involved in the two main carbohydrate/energy-metabolism pathways (pyruvate-dependent and malate-dependent) and drug activation pathways of T. vaginalis , such as the pyruvate:ferredoxin oxidoreductase (PFOR), ferredoxin (Fdx), malic enzyme/malate dehydrogenase (ME/MDH), NADH dehydrogenase, and nitroreductase (NTR) pathways [ 21 , 22 , 23 , 24 ]. 5-nitroimidazole anaerobic resistance in T. vaginalis has also been associated with increased glucose scavenging as well as possible alternative energy pathways involving increased lactate dehydrogenase (LDH) and/or alcohol dehydrogenase (ADH) activities [ 24 , 25 , 26 ]. Aerobic resistance in T. vaginalis is characterized by decreased expression of genes/proteins involved in oxygen scavenging and antioxidant defense mechanisms, such as flavin reductase 1 (FR1), thioredoxin reductase (TrxR), and thioredoxin peroxidase (TrxP) in addition to superoxide dismutase (SOD) and NADH oxidase [ 20 , 25 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Trichomonas vaginalis 5-Nitroimidazole Resistance Targets

et al. 2023

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Trichomonas vaginalis is the most common non-viral sexually transmitted infection. 5-nitroimidazoles are the only FDA-approved medications for T. vaginalis treatment. However, 5-nitroimidazole resistance has been increasingly recognized and may occur in up to 10% of infections. We aimed to delineate mechanisms of T. vaginalis resistance using transcriptome profiling of metronidazole (MTZ)-resistant and sensitive T. vaginalis clinical isolates. In vitro, 5-nitroimidazole susceptibility testing was performed to determine minimum lethal concentrations (MLCs) for T. vaginalis isolates obtained from women who had failed treatment (n = 4) or were successfully cured (n = 4). RNA sequencing, bioinformatics, and biostatistical analyses were performed to identify differentially expressed genes (DEGs) in the MTZ-resistant vs. sensitive T. vaginalis isolates. RNA sequencing identified 304 DEGs, 134 upregulated genes and 170 downregulated genes in the resistant isolates. Future studies with more T. vaginalis isolates with a broad range of MLCs are needed to determine which genes may represent the best alternative targets in drug-resistant strains.

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Unexpected properties of NADP-dependent secondary alcohol dehydrogenase (ADH-1) in Trichomonas vaginalis and other microaerophilic parasites

Abstract: Graphical abstractCoA inhibits the oxidation of 2-propanol and the reduction of acetaldehyde, acetone and a yet unidentified “background” substrate by ADH-1.

Cited by 8 publications

References 20 publications

A review on metronidazole: an old warhorse in antimicrobial chemotherapy

A review on metronidazole: an old warhorse in antimicrobial chemotherapy

Genetic indicators of drug resistance in the highly repetitive genomes ofTrichomonas vaginalisand other trichomonads

Identification of Trichomonas vaginalis 5-Nitroimidazole Resistance Targets

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