Oxygen affinities of metronidazole-resistant and -sensitive stocks of Giardia intestinalis

Ellis, Jayne E.; Wingfield, Jonathan; Cole, Deborah; Boreham, P. F. L.; Lloyd, David

doi:10.1016/0020-7519(93)90095-g

Cited by 46 publications

(38 citation statements)

References 20 publications

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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: 98%

“…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%

“…A Czechoslovakian study in 1988 showed a decrease in PFOR and hydrogenase activity, but it is unknown whether these are primary or pleiotropic events (33,34). Very few new data have appeared since (52). In principle, both PFOR and hydrogenase could activate the 5-nitroimidazoles via a ferredoxin or perhaps flavodoxin intermediate.…”

Section: Aerobic Versus Anaerobic Drug Resistancementioning

confidence: 99%

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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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Section: Giardia Drug Treatment and Resistancementioning

confidence: 98%

Section: Trichomonas Metabolismmentioning

confidence: 99%

Section: Aerobic Versus Anaerobic Drug Resistancementioning

confidence: 99%

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Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

2001

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“…18,20,151 This characteristic makes Giardia a fearful microorganism, mainly among undernourished people, in whom the malabsorption syndrome is more common. In this scenario, developing and screening new antigiardial drugs seems to be a priority.…”

Section: Dovepressmentioning

confidence: 99%

“…Most drugs used have considerable adverse effects and, most of the time, they are contraindicated. [18][19][20] Furthermore, Giardia seems to have a great ability to resist these agents. 17,19,21,22 In this context, the study of new chemotherapeutic agents plays a fundamental role -along with the reviews of the actually used drugs -in the rationale for treatment of giardiasis on the basis of more consistent data.…”

Section: Introductionmentioning

confidence: 99%

The old and new therapeutic approaches to the treatment of giardiasis: Where are we?

Gomes¹

2009

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Giardia intestinalis escapes oxidative stress by colonizing the small intestine: A molecular hypothesis

et al. 2011

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SummaryGiardia intestinalis is the microaerophilic protozoon causing giardiasis, a common infectious intestinal disease. Giardia possesses an O 2 -scavenging activity likely essential for survival in the host. We report that Giardia trophozoites express the O 2 -detoxifying flavodiiron protein (FDP), detected by immunoblotting, and are able to reduce O 2 to H 2 O rapidly ( 3 lM O 2 3 min 3 10 6 cells at 37 8C) and with high affinity (C 50 5 3.4 6 0.7 lM O 2 ). Following a short-term (minutes) exposure to H 2 O 2 100 lM, the O 2 consumption by the parasites is irreversibly impaired, and the FDP undergoes a degradation, prevented by the proteasome-inhibitor MG132. Instead, H 2 O 2 does not cause degradation or inactivation of the isolated FDP. On the basis of the elevated susceptibility of Giardia to oxidative stress, we hypothesize that the parasite preferentially colonizes the small intestine since, compared with colon, it is characterized by a greater capacity for redox buffering and a lower propensity to oxidative stress.

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Oxygen affinities of metronidazole-resistant and -sensitive stocks of Giardia intestinalis

Cited by 46 publications

References 20 publications

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

The old and new therapeutic approaches to the treatment of giardiasis: Where are we?

Giardia intestinalis escapes oxidative stress by colonizing the small intestine: A molecular hypothesis

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