Drug resistance in liver flukes

Fairweather, Ian; Brennan, Gerard; Hanna, R.E.B.; Robinson, Mark W.; Skuce, Philip

doi:10.1016/j.ijpddr.2019.11.003

Cited by 139 publications

(130 citation statements)

References 279 publications

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“…In the past few years, human lncRNAs have been proposed as drug targets in many diseases, especially in cancer and neurological syndromes 21,[53][54][55] . In parasitic diseases, there is a clear need to develop new and inexpensive drugs, especially with the emerging reports of drug resistance 6,[56][57][58] . We believe that it is time to consider lncRNAs as possible drug targets also in parasitic diseases, especially because they show lower conservation in their primary sequences between species than protein-coding genes 17,19,59,60 , which in principle would reduce side effects in therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA levels can be modulated by 5-azacytidine in Schistosoma mansoni

Amaral

Maciel

Silveira

et al. 2020

Sci Rep

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Schistosoma mansoni is a flatworm that causes schistosomiasis, a neglected tropical disease that affects more than 200 million people worldwide. There is only one drug indicated for treatment, praziquantel, which may lead to parasite resistance emergence. The ribonucleoside analogue 5-azacytidine (5-AzaC) is an epigenetic drug that inhibits S. mansoni oviposition and ovarian development through interference with parasite transcription, translation and stem cell activities. Therefore, studying the downstream pathways affected by 5-AzaC in S. mansoni may contribute to the discovery of new drug targets. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein coding potential that have been involved in reproduction, stem cell maintenance and drug resistance. We have recently published a catalog of lncRNAs expressed in S. mansoni life-cycle stages, tissues and single cells. However, it remains largely unknown if lncRNAs are responsive to epigenetic drugs in parasites. Here, we show by RNA-Seq re-analyses that hundreds of lncRNAs are differentially expressed after in vitro 5-AzaC treatment of S. mansoni females, including intergenic, antisense and sense lncRNAs. Many of these lncRNAs belong to co-expression network modules related to male metabolism and are also differentially expressed in unpaired compared with paired females and ovaries. Half of these lncRNAs possess histone marks at their genomic loci, indicating regulation by histone modification. Among a selected set of 8 lncRNAs, half of them were validated by RT-qPCR as differentially expressed in females, and some of them also in males. Interestingly, these lncRNAs are also expressed in other life-cycle stages. This study demonstrates that many lncRNAs potentially involved with S. mansoni reproductive biology are modulated by 5-AzaC and sheds light on the relevance of exploring lncRNAs in response to drug treatments in parasites.

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Section: Discussionmentioning

confidence: 99%

Long non-coding RNA levels can be modulated by 5-azacytidine in Schistosoma mansoni

Amaral

Maciel

Silveira

et al. 2020

Sci Rep

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“…Anthelmintic resistance is clearly a severe problem in certain parasites and geographic localizations—for example in Australian livestock production—requiring strong advocacy for anthelmintic management and increased support for anthelmintic discovery to overcome this. In addition to soil-transmitted helminths, there is increasing recognition of the food-borne trematode infections and concerns around the development of resistance to triclabendazole ( Fairweather et al, 2020 ). However, in our communications around resistance we must take care not to confound the discussion about anthelmintic resistance, with the concerns around the use of critically important antibiotics in human and veterinary medicine ( Scott et al, 2019 ).…”

Section: Challenge Of Resistance and Ongoing Managementmentioning

confidence: 99%

Where are all the anthelmintics? Challenges and opportunities on the path to new anthelmintics

Nixon

Welz

Woods

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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Control of helminth parasites is a key challenge for human and veterinary medicine. In the absence of effective vaccines and adequate sanitation, prophylaxis and treatment commonly rely upon anthelmintics. There are concerns about the development of drug resistance, side-effects, lack of efficacy and cost-effectiveness that drive the need for new classes of anthelmintics. Despite this need, only three new drug classes have reached the animal market since 2000 and no new classes of anthelmintic have been approved for human use. So where are all the anthelmintics? What are the barriers to anthelmintic discovery, and what emerging opportunities can be used to address this? This was a discussion group focus at the 2019 8th Consortium for Anthelmintic Resistance and Susceptibility (CARS) in Wisconsin, USA. Here we report the findings of the group in the broader context of the human and veterinary anthelmintic discovery pipeline, highlighting challenges unique to antiparasitic drug discovery. We comment on why the development of novel anthelmintics has been so rare. Further, we discuss potential opportunities for drug development moving into the 21st Century.

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“…Three areas that the mechanism of action may play a role in are tubulin binding, altered drug uptake and modified drug metabolism [63]. To date, there is no evidence of any changes to β-tubulin in TCBZ-Resistance flukes, but it is possible that the resistance mechanism is on the altered drug uptake and modified drug metabolism.…”

Section: Mechanism Of Action and Development Of Resistancementioning

confidence: 99%

Triclabendazole for the treatment of human fascioliasis and the threat of treatment failures

Marcos

Maco

Terashima

2020

Expert Review of Anti-infective Therapy

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Introduction: The only drug effective against the infection caused by Fasciola hepatica or F. gigantica is triclabendazole (TCBZ), recommended by the WHO and recently approved by the FDA. Here, we describe the evolution of TCBZ regimens and the emergence of TCBZ failure to Fasciola infection. Areas covered: The present review focuses on the evidence of TCBZ for the treatment of fascioliasis. For acute fascioliasis, there is a lack of studies to measure the presence of eggs of Fasciola in stool samples on the follow-up after initial TCBZ treatment. For chronic fascioliasis, WHO recommends a single oral dose of TCBZ 10mg/kg whereas CDC recommends two doses of TCBZ 10mg/kg 12h apart. Incremental number of treatment failures have been documented worldwide. There are currently no therapeutic alternatives for the treatment of fascioliasis in humans. Expert opinion: Most cases of human fascioliasis are successfully treated with TCBZ, but some continue excreting eggs in the stools despite 1-2 standard of care regimens of TCBZ. A precise regimen is unclear for those patients who fail the initial treatment with TCBZ. Further clinical trials are needed to address the possible TCBZ emerging resistance.

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Drug resistance in liver flukes

Cited by 139 publications

References 279 publications

Long non-coding RNA levels can be modulated by 5-azacytidine in Schistosoma mansoni

Long non-coding RNA levels can be modulated by 5-azacytidine in Schistosoma mansoni

Where are all the anthelmintics? Challenges and opportunities on the path to new anthelmintics

Triclabendazole for the treatment of human fascioliasis and the threat of treatment failures

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