Influence of oxygen on the fermentative metabolism of metronidazole-sensitive and resistant strains of Trichomonas vaginalis

Ellis, Jayne E.; Cole, Deborah; Lloyd, David

doi:10.1016/0166-6851(92)90156-e

Cited by 46 publications

(34 citation statements)

References 27 publications

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“…Also of interest is the enhanced reduction of these compounds when NADPH was used as an electron donor. NADH oxidase did not demonstrate ferre-doxin :NAD(P)+ oxidoreductase activity, since it could not catalyse the transfer of electrons from reduced ferredoxin to NAD(P)+ to regenerate NAD(P)H. Although pure NADH oxidase did not exhibit this activity there is likely to be such an enzyme in the G. duodenalis electron transport pathway analogous to the proposed ferredoxin:NAD+ oxidoreductase in 7: vaginalis hydrogenosomes (Ellis et al, 1992).…”

Section: Discussionmentioning

confidence: 95%

A H₂O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis

Brown

Upcroft

1996

European Journal of Biochemistry

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We describe the purification of a H,O-producing NADH oxidase from the protozoan parasite Giardiu duodenalis. The enzyme is a monomeric flavoprotein containing flavin adenine dinucleotide in a 1 : 1 molar ratio with the polypeptide. The NADH oxidase has an apparent molecular mass of 46 kDa and was homogenous as determined by denaturing gel electrophoresis and N-terminal amino acid sequencing. NADPH could substitute for NADH as an electron donor with a K, value of 4.2 pM for NADH and 16 pM for NADPH (pH 7.8 at room temperature). With oxygen as the primary electron acceptor under aerobic conditions, the pure enzyme did not produce 0;-nor H,O, as stoichiometric products of oxygen reduction, implicating H,O as the end product and obviating the need for superoxide dismutase. The ability to utilise oxygen explains the apparent respiration of the amitochondrial fermentative metabolism of Giardia. Mercurials, flavoantagonists and heavy metals (CU'+ and ZnZ+ ) inhibited this activity. Under anaerobic conditions the enzyme catalysed electron transfer at lower efficiencies to other electron acceptors including nitroblue tetrazolium, potassium ferricyanide, FAD and FMN, using either NADH or NADPH as electron donors. NADPH, however, was a more efficient electron donor. Cytochrome c was not reduced under any assay conditions used. The enzyme reduced the nitrofuran drugs, furazolidone (an antigiardial) and nitrofurantoin, to their toxic radical forms as determined by EPR. Metronidazole, a nitroimidazole, was not reduced. Pure NADH oxidase did not demonstrate ferredoxin:NAD(P) ' oxidoreductase activity since it could not accept electrons from reduced ferredoxin to regenerate NAD(P)H. The G. duodenalis NADH oxidase may, therefore, function as a terminal oxidase, similar to the mitochondria1 cytochrome oxidase, and in the maintenance of an optimum intracellular redox ratio. This report of a flavoenzyme from Giardia places Giardiu close to the anaerobic bacteria in evolutionary terms.

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Section: Discussionmentioning

confidence: 95%

A H₂O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis

Brown

Upcroft

1996

European Journal of Biochemistry

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“…Clinical drug-resistant T. vaginalis isolates show various biochemical changes, e.g., decreased expression of PFOR, ferredoxin, and hydrogenase activities (62,73,168,253); oxygen resistance (80,336); and decreased oxidase activity (336). In addition, highly resistant T. vaginalis clinical isolates possess neither detectable PFOR activity nor PFOR and ferredoxin mRNAs (34,73,169,175,253).…”

Section: Drug Resistance In Trichomonasmentioning

confidence: 99%

Current Therapeutics, Their Problems, and Sulfur-Containing-Amino-Acid Metabolism as a Novel Target against Infections by “Amitochondriate” Protozoan Parasites

2007

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SUMMARY The “amitochondriate” protozoan parasites of humans Entamoeba histolytica, Giardia intestinalis, and Trichomonas vaginalis share many biochemical features, e.g., energy and amino acid metabolism, a spectrum of drugs for their treatment, and the occurrence of drug resistance. These parasites possess metabolic pathways that are divergent from those of their mammalian hosts and are often considered to be good targets for drug development. Sulfur-containing-amino-acid metabolism represents one such divergent metabolic pathway, namely, the cysteine biosynthetic pathway and methionine γ-lyase-mediated catabolism of sulfur-containing amino acids, which are present in T. vaginalis and E. histolytica but absent in G. intestinalis. These pathways are potentially exploitable for development of drugs against amoebiasis and trichomoniasis. For instance, l-trifluoromethionine, which is catalyzed by methionine γ-lyase and produces a toxic product, is effective against T. vaginalis and E. histolytica parasites in vitro and in vivo and may represent a good lead compound. In this review, we summarize the biology of these microaerophilic parasites, their clinical manifestation and epidemiology of disease, chemotherapeutics, the modes of action of representative drugs, and problems related to these drugs, including drug resistance. We further discuss our approach to exploit unique sulfur-containing-amino-acid metabolism, focusing on development of drugs against E. histolytica.

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“…PFOR is not totally downregulated, as in highly resistant T. vaginalis, probably because the enzyme is essential to the glycolytic pathway. In vivo assays suggested that PFOR is downregulated further than the assays executed on extracted enzyme (51,52), implying that a second level of enzyme control may also be acting in the resistant cells (196,218).…”

Section: Giardia Drug Treatment and Resistancementioning

confidence: 99%

“…vaginalis lacks mitochondria and other characteristics of higher eukaryotic respiratory metabolism such as cytochromes and oxidative phosphorylation (51,52). Nutrients are taken up by transport through the cell membrane and by phagocytosis.…”

Section: Trichomonas Metabolismmentioning

confidence: 99%

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

2001

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The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated using laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance

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Influence of oxygen on the fermentative metabolism of metronidazole-sensitive and resistant strains of Trichomonas vaginalis

Cited by 46 publications

References 27 publications

A H₂O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis

A H₂O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis

Current Therapeutics, Their Problems, and Sulfur-Containing-Amino-Acid Metabolism as a Novel Target against Infections by “Amitochondriate” Protozoan Parasites

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

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Influence of oxygen on the fermentative metabolism of metronidazole-sensitive and resistant strains of Trichomonas vaginalis

Cited by 46 publications

References 27 publications

A H2O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis

A H2O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis

Current Therapeutics, Their Problems, and Sulfur-Containing-Amino-Acid Metabolism as a Novel Target against Infections by “Amitochondriate” Protozoan Parasites

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

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A H₂O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis

A H₂O‐Producing NADH Oxidase from the Protozoan Parasite Giardia Duodenalis