ABC multidrug transporters in schistosomes and other parasitic flatworms

Greenberg, Robert M.

doi:10.1016/j.parint.2013.02.006

Cited by 39 publications

(38 citation statements)

References 111 publications

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“…As mentioned above, ivermectin is a substrate for mammalian Pgp at the blood-brain barrier, and it is also a substrate for nematode Pgp. Although they are neither ion channels nor critical components of neuromuscular signaling, evidence is accruing [reviewed in 91, 92, 93] that by modulating effective intra-worm concentrations of compounds, parasite ABC transporters can regulate levels of anthelmintic efficacy. They also appear to play a role in development or maintenance of anthelmintic resistance, and several studies indicate that inhibiting these transporters can overcome resistance.…”

Section: Abc Transportersmentioning

confidence: 99%

Ion Channels and Drug Transporters as Targets for Anthelmintics

Greenberg

2014

Curr Clin Micro Rpt

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Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

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Section: Abc Transportersmentioning

confidence: 99%

Ion Channels and Drug Transporters as Targets for Anthelmintics

Greenberg

2014

Curr Clin Micro Rpt

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“…Most notably, ABC multidrug transporters underlie multidrug resistance, a phenomenon in which cells that develop resistance to a particular drug show simultaneous cross-resistance to several structurally unrelated compounds [37] . ABC transporters have additionally been implicated in insusceptibility to anthelmintics, as changes in expression levels and allele frequencies of Pgp and other ABC transporters are found in parasitic helminths exhibiting reduced drug sensitivity [reviewed in 38] , [39] , [40] , [41] .…”

Section: Introductionmentioning

confidence: 99%

“…Like mammals, schistosomes have genes for a wide variety of ABC transporters, including Pgp, MRP1, and BCRP [41] , [42] . Previous work has focused on particular S. mansoni orthologs of Pgp (SMDR2) and MRP1 (SmMRP1), and the role they may play in the parasite's physiology and susceptibility to PZQ.…”

Section: Introductionmentioning

confidence: 99%

Inhibition or Knockdown of ABC Transporters Enhances Susceptibility of Adult and Juvenile Schistosomes to Praziquantel

et al. 2014

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Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease that affects hundreds of millions. Treatment of schistosomiasis depends almost entirely on the drug praziquantel (PZQ). Though essential to treating and controlling schistosomiasis, a major limitation of PZQ is that it is not active against immature mammalian-stage schistosomes. Furthermore, there are reports of field isolates with heritable reductions in PZQ susceptibility, and researchers have selected for PZQ-resistant schistosomes in the laboratory. P-glycoprotein (Pgp; ABCB1) and other ATP binding cassette (ABC) transporters remove a wide variety of toxins and xenobiotics from cells, and have been implicated in multidrug resistance (MDR). Changes in ABC transporter structure or expression levels are also associated with reduced drug susceptibility in parasitic helminths, including schistosomes. Here, we show that the activity of PZQ against schistosome adults and juveniles ex vivo is potentiated by co-administration of either the highly potent Pgp inhibitor tariquidar or combinations of inhibitors targeting multiple ABC multidrug transporters. Adult worms exposed to sublethal PZQ concentrations remain active, but co-administration of ABC transporter inhibitors results in complete loss of motility and disruption of the tegument. Notably, juvenile schistosomes (3–4 weeks post infection), normally refractory to 2 µM PZQ, become paralyzed when transporter inhibitors are added in combination with the PZQ. Experiments using the fluorescent PZQ derivative (R)-PZQ-BODIPY are consistent with the transporter inhibitors increasing effective intraworm concentrations of PZQ. Adult worms in which expression of ABC transporters has been suppressed by RNA interference show increased responsiveness to PZQ and increased retention of (R)-PZQ-BODIPY consistent with an important role for these proteins in setting levels of PZQ susceptibility. These results indicate that parasite ABC multidrug transporters might serve as important targets for enhancing the action of PZQ. They also suggest a potentially novel and readily-available strategy for overcoming reduced PZQ susceptibility of schistosomes.

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“…ATP-binding cassette (ABC) transporter proteins are efflux pumps that have relevance to multidrug resistance in nematodes and schistosomes [26]. A total number of 19 six-transmembrane helix ABC transporter domains (InterPro:IPR001140, Pfam: PF00664) were detected in E. multilocularis predicted gene transcripts, whereas a total of 37 of these domains were present in S. erinaceieuropaei predicted transcripts.…”

Section: Resultsmentioning

confidence: 99%

The genome of the sparganosis tapeworm Spirometra erinaceieuropaei isolated from the biopsy of a migrating brain lesion

et al. 2014

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Background: Sparganosis is an infection with a larval Diphyllobothriidea tapeworm. From a rare cerebral case presented at a clinic in the UK, DNA was recovered from a biopsy sample and used to determine the causative species as Spirometra erinaceieuropaei through sequencing of the cox1 gene. From the same DNA, we have produced a draft genome, the first of its kind for this species, and used it to perform a comparative genomics analysis and to investigate known and potential tapeworm drug targets in this tapeworm. Results: The 1.26 Gb draft genome of S. erinaceieuropaei is currently the largest reported for any flatworm. Through investigation of β-tubulin genes, we predict that S. erinaceieuropaei larvae are insensitive to the tapeworm drug albendazole. We find that many putative tapeworm drug targets are also present in S. erinaceieuropaei, allowing possible cross application of new drugs. In comparison to other sequenced tapeworm species we observe expansion of protease classes, and of Kuntiz-type protease inhibitors. Expanded gene families in this tapeworm also include those that are involved in processes that add post-translational diversity to the protein landscape, intracellular transport, transcriptional regulation and detoxification.

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ABC multidrug transporters in schistosomes and other parasitic flatworms

Cited by 39 publications

References 111 publications

Ion Channels and Drug Transporters as Targets for Anthelmintics

Ion Channels and Drug Transporters as Targets for Anthelmintics

Inhibition or Knockdown of ABC Transporters Enhances Susceptibility of Adult and Juvenile Schistosomes to Praziquantel

The genome of the sparganosis tapeworm Spirometra erinaceieuropaei isolated from the biopsy of a migrating brain lesion

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