The Small Molecule Triclabendazole Decreases the Intracellular Level of Cyclic AMP and Increases Resistance to Stress in Saccharomyces cerevisiae

Lee, Yong Joo; Shi, Runhua; Witt, Stephan N.

doi:10.1371/journal.pone.0064337

Cited by 8 publications

(8 citation statements)

References 51 publications

(51 reference statements)

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“…Recently, TCBZ was reported to inhibit adenylate cyclase activity in yeast and/or inhibit the association of GTP-Ras with adenylate cyclase [47]. Interestingly, F. hepatica has one of the most active adenylate cyclase activities in biology and this activity is associated with the parasite's membrane fraction [48].…”

Section: Biochemistry Of Tcbz Actionmentioning

confidence: 99%

Current Threat of Triclabendazole Resistance in Fasciola hepatica

Kelley

Elliott

Beddoe

et al. 2016

Trends in Parasitology

246

185

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Triclabendazole (TCBZ) is the only chemical that kills early immature and adult Fasciola hepatica (liver fluke) but widespread resistance to the drug greatly compromises fluke control in livestock and humans. The mode of action of TCBZ and mechanism(s) underlying parasite resistance to the drug are not known. Due to the high prevalence of TCBZ resistance (TCBZ-R), effective management of drug resistance is now critical for sustainable livestock production. Here, we discuss the current status of TCBZ-R in F. hepatica, the global distribution of resistance observed in livestock, the possible mechanism(s) of drug action, the proposed mechanisms and genetic basis of resistance, and the prospects for future control of liver fluke infections using an integrated parasite management (IPM) approach.

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Section: Biochemistry Of Tcbz Actionmentioning

confidence: 99%

Current Threat of Triclabendazole Resistance in Fasciola hepatica

Kelley

Elliott

Beddoe

et al. 2016

Trends in Parasitology

246

185

View full text Add to dashboard Cite

show abstract

“…Recently it was reported that TCBZ can inhibit adenylate cyclase (AC) activity in yeast [ 32 ], but despite being widely studied in F. hepatica [ 80 ], there are still no in vitro studies of AC variation in response to drug administration. To gain insight into this possible mechanism, we investigated if AC expression was skewed in our samples.…”

Section: Resultsmentioning

confidence: 99%

“…The role of microtubules in TCBZ pathogenesis was further suggested by several lines of evidence, like the detection of cell division inhibition in vitelline and reproductive cells [ 27 – 29 ], the reduction in the transport of tegumental secretory bodies [ 22 ], and the inhibition of tubulin immunostaining [ 30 , 31 ]. Surprisingly, TCBZ was recently reported to inhibit adenylate cyclase activity in yeast, activating the stress response [ 32 ]. This effect has not been observed in the liver fluke so far, but considering the role of cAMP as second messenger, it might provide an explanation for the pleiotropic effects of the drug.…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic alterations in gene expression in Latin American Fasciola hepatica isolates with different susceptibility to drugs

et al. 2018

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BackgroundFasciola hepatica is the main agent of fasciolosis, a zoonotic disease affecting livestock worldwide, and an emerging food-borne disease in humans. Even when effective treatments are available, drugs are costly and can result in tolerance, liver damage and normally they do not prevent reinfection. Drug-resistant strains in livestock have been reported in various countries and, more worryingly, drug resistance in human cases has emerged in South America. The present study aims to characterize the transcriptome of two South American resistant isolates, the Cajamarca isolate from Peru, resistant to both triclabendazole and albendazole (TCBZR/ABZR) and the Rubino isolate from Uruguay, resistant to ABZ (TCBZS/ABZR), and compare them to a sensitive strain (Cenapa, Mexico, TCBZS/ABZS) to reveal putative molecular mechanisms leading to drug resistance.ResultsWe observed a major reduction in transcription in the Cajamarca TCBZR/ABZR isolate in comparison to the other isolates. While most of the differentially expressed genes are still unannotated, several trends could be detected. Specific reduction in the expression levels of cytoskeleton proteins was consistent with a role of tubulins as putative targets of triclabendazole (TCBZ). A marked reduction of adenylate cyclase might be underlying pleiotropic effects on diverse metabolic pathways of the parasite. Upregulation of GST mu isoforms suggests this detoxifying mechanism as one of the strategies associated with resistance.ConclusionsOur results stress the value of transcriptomic approaches as a means of providing novel insights to advance the understanding of drug mode of action and drug resistance. The results provide evidence for pleiotropic variations in drug-resistant isolates consistent with early observations of TCBZ and ABZ effects and recent proteomic findings.Electronic supplementary materialThe online version of this article (10.1186/s13071-017-2553-2) contains supplementary material, which is available to authorized users.

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“…Most of the studies on the mechanism of action of TCBZ have been carried out with TCBZ.SO. The precise mechanism remains to be fully elucidated, but there is more evidence for an action against microtubules and microtubule-based processes than for other possibilities, such as against energy metabolism or neuromuscular co-ordination [28].…”

Section: Mechanism Of Action Of Triclabendazolementioning

confidence: 99%

Review on Triclabendazole Resistance in Fasciola

2020

J Vet Sci Med

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The control of Fasciolosis can be achieved by application of anthelmintic drugs, elimination of the number of intermediate hosts and reduction of exposure to infection. Triclabendazole, which is a member of Benzimidazole, is most recommended and effective way of controlling fasciolosis in animals and humans that can kill both mature (adult) and immature liver flukes. This drug have able to penetrate the tegument of Fasciola (F) hepatica by diffusion, and the fluke is able to sulfoxidate the drug to the active sulfoxide metabolite which binds to β-tubulin and thus inhibit the formation of microtubules that are components of cytoskeleton of the parasite. However, in recent year, resistance of Triclabendazole is reported in animals and humans in different regions of the world. Resistance has likely appeared due to a generally poor understanding of liver fluke biology by farmers and con-founding factors, such as incorrect dosing, inappropriate product choice, and lack of testing for efficacy. These conditions may lead to reduced diffusion and metabolism of the drug, change efflux pump activity and changes in the target molecule that can reduce the effectiveness of Triclabendazole. Both in-vivo and in-vitro methods, like Faecal Egg Count Reduction Test (FECRT) and the Egg Hatch Assay (EHA), respectively, can help to investigate the resistance of Triclabendazole. Administration of dual active flukicide drugs, development of vaccines, implementation of Fasciola control methods other than Triclabendazole, and use of accurate dosage at appropriate time can help to reduce the incidence of Triclabendazole resistance.

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The Small Molecule Triclabendazole Decreases the Intracellular Level of Cyclic AMP and Increases Resistance to Stress in Saccharomyces cerevisiae

Cited by 8 publications

References 51 publications

Current Threat of Triclabendazole Resistance in Fasciola hepatica

Current Threat of Triclabendazole Resistance in Fasciola hepatica

Pleiotropic alterations in gene expression in Latin American Fasciola hepatica isolates with different susceptibility to drugs

Review on Triclabendazole Resistance in Fasciola

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