Albendazole Resistance in<i>Giardia</i>Is Correlated with Cytoskeletal Changes but Not with a Mutation at Amino Acid 200 in β-Tubulin

Upcroft, Jacqueline; Mitchell, Richard R.; Chen, Nanhua; Upcroft, Peter

doi:10.1089/mdr.1996.2.303

Cited by 64 publications

(38 citation statements)

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“…In vitro development of albendazole resistance was also reported (180,309). Albendazole resistance developed more easily in a furazolidone-resistant strain, giving rise to a multidrug-resistant phenotype (309).…”

Section: Drug Resistance In G Intestinalismentioning

confidence: 92%

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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Section: Drug Resistance In G Intestinalismentioning

confidence: 92%

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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“…Like metronidazole, resistance of Giardia to albendazole has been reported to occur readily in vitro (111,206). Albendazole resistance also developed more readily in a furazolidone-resistant strain, and therefore these strains are multidrug resistant (206,218). A giardiasis patient with parasites refractory to metronidazole and albendazole administered separately was successfully treated with these drugs administered together (unpublished data).…”

Section: Giardia Drug Treatment and Resistancementioning

confidence: 95%

“…Albendazole eventually may be accepted as an alternative to metronidazole, particularly in cases of metronidazole failure, if current levels of albendazole resistance or treatment failure do not increase further. Like metronidazole, resistance of Giardia to albendazole has been reported to occur readily in vitro (111,206). Albendazole resistance also developed more readily in a furazolidone-resistant strain, and therefore these strains are multidrug resistant (206,218).…”

Section: Giardia Drug Treatment and Resistancementioning

confidence: 99%

“…This activity has different substrate requirements, principally 2-ketobutyrate, does not neccessarily donate electrons to ferredoxins, and appears to bypass the activation of metronidazole because of a higher redox potential (216). Albendazole resistance was easier to induce in metronidazole-resistant Giardia (206), producing a multidrug resistance phenotype. Although the cytoskeletal structure was changed in albendazole-resistant lines, the common mutation seen in other organisms resistant to albendazole in ␤-tubulin at amino acid position 200 was not observed, suggesting an alternative mechanism of resistance.…”

Section: Giardia Drug Treatment and Resistancementioning

confidence: 99%

“…Stepwise incremental increases in drug resistance induced by a variety of drug regimens, including increases in drug concentration at sublethal levels or short multiple exposures to lethal levels, that are administered with and without mutagens, have provided considerable information about the ability of parasites to mount a resistance defense and the mechanisms involved (22,24,25,33,34,101,193,194,195,196,200,201,206,208,216,217,218). With no examples of horizontal, transposon, or plasmid transfer of drug resistance in the anaerobic protozoa, this has been a valid and extremely useful approach to determine mechanisms of resistance.…”

Section: Clinical and Laboratory-generated Drug-resistant Isolatesmentioning

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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My favorite cell: Giardia

Upcroft

1998

Bioessays

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The gut protozoan parasite, Giardia duodenalis, is the best characterized example of the most ancient eukaryotes, which are anaerobic and appear to be primitively amitochondrial. Apart from its obvious medical importance, Giardia is fascinating in its own right. Its prokaryotic‐like anaerobic metabolism renders it selectively sensitive to some bacterial drugs, especially the nitroimidazoles, which are activated to form toxic radicals. Other features, including an enzyme that reduces oxygen directly to water, cysteine as the keeper of redox balance, a plasmid, and toxin‐like genes are also distinctly prokaryotic‐like. But, unlike prokaryotes, Giardia has a sophisticated, highly developed cytoskeleton, bounded nuclei, linear chromosomes capped with telomeric repeats, and telomere positional regulation of gene expression. BioEssays 20:256–263, 1998.© 1998 John Wiley & Sons, Inc.

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Albendazole Resistance inGiardiaIs Correlated with Cytoskeletal Changes but Not with a Mutation at Amino Acid 200 in β-Tubulin

Cited by 64 publications

References 40 publications

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

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

My favorite cell: Giardia

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