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David Leitsch - One of the best experts on this subject based on the ideXlab platform.
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nitroimidazole drugs vary in their mode of action in the human parasite giardia lamblia
International Journal for Parasitology-Drugs and Drug Resistance, 2012Co-Authors: David Leitsch, Sarah Schlosser, Anita Burgess, Michael DuchêneAbstract:Giardia lamblia (syn. duodenalis, intestinalis) is a globally occurring micro-aerophilic human parasite that causes gastrointestinal disease. Standard treatment of G. lamblia infections is based on the 5-nitroimidazole drugs metronidazole and tinidazole. In two other micro-aerophilic parasites, Entamoeba histolytica and Trichomonas vaginalis, 5-nitroimidazole drugs bind to proteins involved in the thioredoxin-mediated redox network and disrupt the redox equilibrium by inhibiting thioredoxin reductase and depleting intracellular thiol pools. The major aim of this study was to assess whether Nitroimidazoles exert a similar toxic effect on G. lamblia physiology. The 5-Nitroimidazoles metronidazole and tinidazole were found to bind to the same subset of proteins including thioredoxin reductase. However, in contrast to E. histolytica and T. vaginalis, none of the other proteins bound are candidates for being involved in the thioredoxin-mediated redox network. Translation elongation factor EF-1γ, an essential factor in protein synthesis, was widely degraded upon treatment with 5-Nitroimidazoles. 2-Nitroimidazole (azomycin) and the 5-nitroimidazole ronidazole did not bind to any G. lamblia proteins, which is in contrast to previous findings in E. histolytica and T. vaginalis. All Nitroimidazoles tested reduced intracellular thiol pools in G. lamblia, but metronidazole, also in contrast to the situation in the other two parasites, had the slightest effect. Taken together, our results suggest that nitroimidazole drugs affect G. lamblia in a fundamentally different way than E. histolytica and T. vaginalis.
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disrupted intracellular redox balance of the diplomonad fish parasite spironucleus vortens by 5 Nitroimidazoles and garlic derived compounds
Veterinary Parasitology, 2012Co-Authors: Catrin Ffion Williams, Kathirvel Alagesan, Michael Duchêne, Daniel Kolarich, Joanne Cable, David R. Williams, David LeitschAbstract:The 5-nitroimidazole, metronidazole, has traditionally been employed in veterinary medicine to treat a range of infections including the diplomonad fish parasite Spironucleus. This study aims to determine the mode of action of metronidazole on Spironucleus vortens, including the specific mechanism of activation of the pro-drug and subsequent cellular targets of the drug metabolites. Due to the ban on use of metronidazole in the treatment of production animals in Europe and USA, garlic-derived compounds were also investigated as natural alternatives to metronidazole chemotherapy. Scanning electron microscopy (SEM) provided an overview of gross cellular damage caused by metronidazole and garlic derivatives. Proteomic analyses by 2D gel electrophoresis identified the proteins involved in specific covalent adduct formation with Nitroimidazoles. Furthermore, thioredoxin reductase (TrxR) activity and non-protein thiol concentration were assayed in extracts of S. vortens before and after treatment with Nitroimidazoles and garlic-derivatives. Metronidazole and garlic-derived compounds caused severe damage of trophozoites indicated by membrane blebbing and lysed cell debris. Analysis of the S. vortens proteome identified several proteins capable of specific nitroimidazole binding, including; uridine phosphorylase, enolase, protein disulphide isomerase, aminoacyl-histidine dipeptidase and malic enzyme. Of the compounds tested, metronidazole and the garlic-derived compound ajoene were the most effective at inhibiting TrxR activity and depleting non-protein thiols. These data suggest TrxR-mediated activation of Nitroimidazoles, leading to depletion of non-protein thiols. Redox imbalance due to antioxidant failure is implicated as the mode of action of Nitroimidazoles and garlic-derived compounds, ultimately leading to cell death. Possible synergy between garlic derivatives and metronidazole should be further investigated in vitro in order to determine their theoretical implications.
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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, 2009Co-Authors: David Leitsch, Johannes Stadlmann, Friedrich Altmann, Marina Binder, Daniel Kolarich, Michael DuchêneAbstract:Summary Infections with the microaerophilic parasite Trichomonas vaginalis are treated with the 5-nitroimidazole drug metronidazole, which is also in use against Entamoeba histolytica, Giardia intestinalis and microaerophilic/anaerobic bacteria. Here we report that in T. vaginalis the flavin enzyme thioredoxin reductase displays nitroreductase activity with Nitroimidazoles, including metronidazole, and with the nitrofuran drug furazolidone. Reactive metabolites of metronidazole and other Nitroimidazoles form covalent adducts with several proteins that are known or assumed to be associated with thioredoxin-mediated redox regulation, including thioredoxin reductase itself, ribonucleotide reductase, thioredoxin peroxidase and cytosolic malate dehydrogenase. Disulphide reducing activity of thioredoxin reductase was greatly diminished in extracts of metronidazole-treated cells and intracellular non-protein thiol levels were sharply decreased. We generated a highly metronidazole-resistant cell line that displayed only minimal thioredoxin reductase activity, not due to diminished expression of the enzyme but due to the lack of its FAD cofactor. Reduction of free flavins, readily observed in metronidazole-susceptible cells, was also absent in the resistant cells. On the other hand, iron-depleted T. vaginalis cells, expressing only minimal amounts of PFOR and hydrogenosomal malate dehydrogenase, remained fully susceptible to metronidazole. Thus, taken together, our data suggest a flavin-based mechanism of metronidazole activation and thereby challenge the current model of hydrogenosomal activation of nitroimidazole drugs.
Michael Duchêne - One of the best experts on this subject based on the ideXlab platform.
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nitroimidazole drugs vary in their mode of action in the human parasite giardia lamblia
International Journal for Parasitology-Drugs and Drug Resistance, 2012Co-Authors: David Leitsch, Sarah Schlosser, Anita Burgess, Michael DuchêneAbstract:Giardia lamblia (syn. duodenalis, intestinalis) is a globally occurring micro-aerophilic human parasite that causes gastrointestinal disease. Standard treatment of G. lamblia infections is based on the 5-nitroimidazole drugs metronidazole and tinidazole. In two other micro-aerophilic parasites, Entamoeba histolytica and Trichomonas vaginalis, 5-nitroimidazole drugs bind to proteins involved in the thioredoxin-mediated redox network and disrupt the redox equilibrium by inhibiting thioredoxin reductase and depleting intracellular thiol pools. The major aim of this study was to assess whether Nitroimidazoles exert a similar toxic effect on G. lamblia physiology. The 5-Nitroimidazoles metronidazole and tinidazole were found to bind to the same subset of proteins including thioredoxin reductase. However, in contrast to E. histolytica and T. vaginalis, none of the other proteins bound are candidates for being involved in the thioredoxin-mediated redox network. Translation elongation factor EF-1γ, an essential factor in protein synthesis, was widely degraded upon treatment with 5-Nitroimidazoles. 2-Nitroimidazole (azomycin) and the 5-nitroimidazole ronidazole did not bind to any G. lamblia proteins, which is in contrast to previous findings in E. histolytica and T. vaginalis. All Nitroimidazoles tested reduced intracellular thiol pools in G. lamblia, but metronidazole, also in contrast to the situation in the other two parasites, had the slightest effect. Taken together, our results suggest that nitroimidazole drugs affect G. lamblia in a fundamentally different way than E. histolytica and T. vaginalis.
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disrupted intracellular redox balance of the diplomonad fish parasite spironucleus vortens by 5 Nitroimidazoles and garlic derived compounds
Veterinary Parasitology, 2012Co-Authors: Catrin Ffion Williams, Kathirvel Alagesan, Michael Duchêne, Daniel Kolarich, Joanne Cable, David R. Williams, David LeitschAbstract:The 5-nitroimidazole, metronidazole, has traditionally been employed in veterinary medicine to treat a range of infections including the diplomonad fish parasite Spironucleus. This study aims to determine the mode of action of metronidazole on Spironucleus vortens, including the specific mechanism of activation of the pro-drug and subsequent cellular targets of the drug metabolites. Due to the ban on use of metronidazole in the treatment of production animals in Europe and USA, garlic-derived compounds were also investigated as natural alternatives to metronidazole chemotherapy. Scanning electron microscopy (SEM) provided an overview of gross cellular damage caused by metronidazole and garlic derivatives. Proteomic analyses by 2D gel electrophoresis identified the proteins involved in specific covalent adduct formation with Nitroimidazoles. Furthermore, thioredoxin reductase (TrxR) activity and non-protein thiol concentration were assayed in extracts of S. vortens before and after treatment with Nitroimidazoles and garlic-derivatives. Metronidazole and garlic-derived compounds caused severe damage of trophozoites indicated by membrane blebbing and lysed cell debris. Analysis of the S. vortens proteome identified several proteins capable of specific nitroimidazole binding, including; uridine phosphorylase, enolase, protein disulphide isomerase, aminoacyl-histidine dipeptidase and malic enzyme. Of the compounds tested, metronidazole and the garlic-derived compound ajoene were the most effective at inhibiting TrxR activity and depleting non-protein thiols. These data suggest TrxR-mediated activation of Nitroimidazoles, leading to depletion of non-protein thiols. Redox imbalance due to antioxidant failure is implicated as the mode of action of Nitroimidazoles and garlic-derived compounds, ultimately leading to cell death. Possible synergy between garlic derivatives and metronidazole should be further investigated in vitro in order to determine their theoretical implications.
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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, 2009Co-Authors: David Leitsch, Johannes Stadlmann, Friedrich Altmann, Marina Binder, Daniel Kolarich, Michael DuchêneAbstract:Summary Infections with the microaerophilic parasite Trichomonas vaginalis are treated with the 5-nitroimidazole drug metronidazole, which is also in use against Entamoeba histolytica, Giardia intestinalis and microaerophilic/anaerobic bacteria. Here we report that in T. vaginalis the flavin enzyme thioredoxin reductase displays nitroreductase activity with Nitroimidazoles, including metronidazole, and with the nitrofuran drug furazolidone. Reactive metabolites of metronidazole and other Nitroimidazoles form covalent adducts with several proteins that are known or assumed to be associated with thioredoxin-mediated redox regulation, including thioredoxin reductase itself, ribonucleotide reductase, thioredoxin peroxidase and cytosolic malate dehydrogenase. Disulphide reducing activity of thioredoxin reductase was greatly diminished in extracts of metronidazole-treated cells and intracellular non-protein thiol levels were sharply decreased. We generated a highly metronidazole-resistant cell line that displayed only minimal thioredoxin reductase activity, not due to diminished expression of the enzyme but due to the lack of its FAD cofactor. Reduction of free flavins, readily observed in metronidazole-susceptible cells, was also absent in the resistant cells. On the other hand, iron-depleted T. vaginalis cells, expressing only minimal amounts of PFOR and hydrogenosomal malate dehydrogenase, remained fully susceptible to metronidazole. Thus, taken together, our data suggest a flavin-based mechanism of metronidazole activation and thereby challenge the current model of hydrogenosomal activation of nitroimidazole drugs.
Cynthia S. Dowd - One of the best experts on this subject based on the ideXlab platform.
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Structure−Activity Relationships of Antitubercular Nitroimidazoles. 1. Structural Features Associated with Aerobic and Anaerobic Activities of 4- and 5-Nitroimidazoles
Journal of Medicinal Chemistry, 2009Co-Authors: Liang Zhang, Ujjini H. Manjunatha, Sejal J. Patel, Jan Jiricek, Thomas H Keller, Helena I. Boshoff, Clifton E. Barry, Ramandeep Singh, Cynthia S. DowdAbstract:The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-Nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-Nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-Nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-Nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficienc...
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Structure−Activity Relationships of Antitubercular Nitroimidazoles. 1. Structural Features Associated with Aerobic and Anaerobic Activities of 4- and 5-Nitroimidazoles
Journal of medicinal chemistry, 2009Co-Authors: Pilho Kim, Ujjini H. Manjunatha, Jan Jiricek, Thomas H Keller, Helena I. Boshoff, Clifton E. Barry, Ramandeep Singh, Liang Zhang, Sejal Patel, Cynthia S. DowdAbstract:The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-Nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-Nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-Nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-Nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved Nitroimidazoles.
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structure activity relationships of antitubercular Nitroimidazoles 1 structural features associated with aerobic and anaerobic activities of 4 and 5 Nitroimidazoles
Journal of Medicinal Chemistry, 2009Co-Authors: Pilho Kim, Ujjini H. Manjunatha, Jan Jiricek, Thomas H Keller, Helena I. Boshoff, Clifton E. Barry, Ramandeep Singh, Liang Zhang, Sejal Patel, Cynthia S. DowdAbstract:The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-Nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-Nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-Nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-Nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved Nitroimidazoles.
Johanna L Matus - One of the best experts on this subject based on the ideXlab platform.
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Validation of a new screening, determinative, and confirmatory multi-residue method for Nitroimidazoles and their hydroxy metabolites in turkey muscle tissue by liquid chromatography-tandem mass spectrometry.
Drug Testing and Analysis, 2012Co-Authors: Joe O Boison, Philip A Asea, Johanna L MatusAbstract:A new and sensitive multi-residue method (MRM) with detection by LC-MS/MS was developed and validated for the screening, determination, and confirmation of residues of 7 Nitroimidazoles and 3 of their metabolites in turkey muscle tissues at concentrations ≥ 0.05 ng/g. The compounds were extracted into a solvent with an alkali salt. Sample clean-up and concentration was then done by solid-phase extraction (SPE) and the compounds were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The characteristic parameters including repeatability, selectivity, ruggedness, stability, level of quantification, and level of confirmation for the new method were determined. Method validation was achieved by independent verification of the parameters measured during method characterization. The seven Nitroimidazoles included are metronidazole (MTZ), ronidazole (RNZ), dimetridazole (DMZ), tinidazole (TNZ), ornidazole (ONZ), ipronidazole (IPR), and carnidazole (CNZ). It was discovered during the single laboratory validation of the method that five of the seven Nitroimidazoles (i.e. metronidazole, dimetridazole, tinidazole, ornidazole and ipronidazole) and the 3 metabolites (1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (MTZ-OH), 2-hydroxymethyl-1-methyl-5-nitroimidazole (HMMNI, the common metabolite of ronidazole and dimetridazole), and 1-methyl-2-(2'-hydroxyisopropyl)-5-nitroimidazole (IPR-OH) included in this study could be detected, confirmed, and quantified accurately whereas RNZ and CNZ could only be detected and confirmed but not accurately quantified. © Her Majesty the Queen in Right of Canada as Represented by the Minister of Agriculture and Agri-food Canada 2012.
Stephan Denifl - One of the best experts on this subject based on the ideXlab platform.
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Fragmentation patterns of 4(5)-nitroimidazole and 1-methyl-5-nitroimidazole-The effect of the methylation
Journal of Mass Spectrometry, 2017Co-Authors: E. Itälä, Katrin Tanzer, S. Granroth, Kuno Kooser, Stephan Denifl, Edwin KukkAbstract:We present here the photofragmentation patterns of doubly ionized 4(5)-nitroimidazole and 1-methyl-5-nitroimidazole. The doubly ionized state was created by core ionizing the C 1s orbitals of the samples, rapidly followed by Auger decay. Due to the recent development of nitroimidazole-based radiosensitizing drugs, core ionization was selected as it represents the very same processes taking place under the irradiation with medical X-rays. In addition to the fragmentation patterns of the sample, we study the effects of methylation on the fragmentation patterns of Nitroimidazoles. We found that methylation alters the fragmentation significantly, especially the charge distribution between the final fragments. The most characteristic feature of the methylation is that it effectively quenches the production of NO and NO+, widely regarded as key radicals in the chemistry of radiosensitization by the Nitroimidazoles.
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Isomer Selectivity in Low-Energy Electron Attachment to Nitroimidazoles.
Chemistry: A European Journal, 2017Co-Authors: Anita Ribar, Katharina Fink, Michael Probst, Stefan Huber, Linda Feketeová, Stephan DeniflAbstract:: Low-energy electrons effectively decompose the isomers 2-nitroimidazole and 4(5)-nitroimidazole by dissociative electron attachment (DEA) into a variety of fragment anions and radicals. The present study shows that a distinct selectivity for the two isomers occurs in the DEA reactions. Several new decay channels are observed for 2-nitroimidazole, including a dominant one leading to the loss of molecular H2 O by attachment of a low-energy electron. In contrast, the loss of a single hydrogen atom is a much more efficient reaction in DEA to 4(5)-nitroimidazole. Quantum chemical calculations were carried out to explain the pronounced isomer effect found in the DEA experiment. Although the free energies of the reactions are similar for the different isomers, the very different natures of the dipole-bound states and valence-bound anions lead to preference for or hindrance of a particular dissociation channel. Nitroimidazolic compounds are considered as radiosensitizing compounds in tumor radiation therapy. The enhanced formation of fragments, including the highly reactive hydroxyl radical, in DEA to 2-nitroimidazole suggests that it may be a more efficient radiosensitizing agent than 4(5)-Nitroimidazoles.