The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

Tompkins, Jeffrey B.; Stitt, Laurel E.; Morrissette, Alana M.; Ardelli, Bernadette F.

doi:10.1007/s00436-011-2378-4

Cited by 19 publications

(16 citation statements)

References 60 publications

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“…Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8)(9)(10)(11)(12)(13), and they are involved in the tolerance of Caenorhabditis elegans (9,(14)(15)(16) and parasitic nematodes such as Haemonchus contortus or Cooperia oncophora (13,(17)(18)(19)(20) to MLs. In addition, mutation of the dyf-7 gene was associated with an IVM resistance phenotype in C. elegans and in H. contortus, leading to an abnormal dendritic morphology of amphid sensory neurons, as revealed by a dye-filling-defective phenotype (21).…”

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confidence: 99%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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cIvermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans. C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild-type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin-and moxidectin-selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin-and moxidectin-selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin-and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin.T he broad-spectrum anthelmintic macrocyclic lactones (MLs) are most commonly used in veterinary medicine to treat diseases caused by gastrointestinal nematodes and external parasites in livestock (1, 2). Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4-7). Discovering the mechanisms by which resistance to MLs occurs remains an important challenge today.There is consistent evidence that ATP-binding-cassette (ABC) transporters such as P-glycoproteins (Pgps) play an important role in multidrug resistance (MDR) in many organisms, including several nematode species. Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8-13), and they are involved in the tolerance of Caenorhabditis elegans (9, 14-16) and parasitic nematodes s...

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confidence: 99%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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“…A significant increase in the expression profiles of Cel -pgp-11, Cel -haf-1, Cel- mrp-1, Cel- mrp-5, Cel- mrp-7 after IVM treatment (Yan et al., 2012, Ardelli and Prichard, 2013, Bygarski et al., 2014) was reported in an IVM-resistant strain, compared to the wild-type Bristol N2 strain. Sensitivity to ivermectin was increased by MDR inhibitors in B. malayi (Tompkins et al., 2011). P-glycoproteins of D. immitis could also be interesting targets for new anthelmintic drugs, considering the physiological roles their homologs play in other nematodes, including C. elegans .…”

Section: Discussionmentioning

confidence: 99%

“…In nematodes, multidrug resistance is suggested to be conferred by members from subfamily B and C, though many reports specifically implicate the role of PGPs in the resistance mechanism (Prichard et al., 2012 Lespine et al., 2012). A study in B. malayi has shown that transporters from subfamily A and G may also have a role in resistance, as they were also overexpressed along with PGPs and MRPs following treatment with ivermectin and moxidectin (Stitt et al., 2011, Tompkins et al., 2011). …”

Section: Introductionmentioning

confidence: 99%

“…Also, substrates of PGP that are competitive inhibitors (e.g., verapamil), or that block the transport function directly, have restored anthelmintic sensitivity (Ardelli and Prichard, 2013). In B. malayi , ABC transporter inhibitors have potentiated sensitivity to ivermectin (Tompkins et al., 2011). Similar reversal mechanisms have been shown for H. contortus resistant to ivermectin (Molento and Prichard, 1999, Lifschitz et al., 2010, Bartley et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

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Polymorphism in ABC transporter genes of Dirofilaria immitis

Mani

Bourguinat

Prichard

2017

International Journal for Parasitology: Drugs and Drug Resistan

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Dirofilaria immitis, a filarial nematode, causes dirofilariasis in dogs, cats and occasionally in humans. Prevention of the disease has been mainly by monthly use of the macrocyclic lactone (ML) endectocides during the mosquito transmission season. Recently, ML resistance has been confirmed in D. immitis and therefore, there is a need to find new classes of anthelmintics. One of the mechanisms associated with ML resistance in nematodes has been the possible role of ATP binding cassette (ABC) transporters in reducing drug concentrations at receptor sites. ABC transporters, mainly from sub-families B, C and G, may contribute to multidrug resistance (MDR) by active efflux of drugs out of the cell. Gene products of ABC transporters may thus serve as the targets for agents that may modulate susceptibility to drugs, by inhibiting drug transport. ABC transporters are believed to be involved in a variety of physiological functions critical to the parasite, such as sterol transport, and therefore may also serve as the target for drugs that can act as anthelmintics on their own. Knowledge of polymorphism in these ABC transporter genes in nematode parasites could provide useful information for the process of drug design. We have identified 15 ABC transporter genes from sub-families A, B, C and G, in D. immitis, by comparative genomic approaches and analyzed them for polymorphism. Whole genome sequencing data from four ML susceptible (SUS) and four loss of efficacy (LOE) pooled populations were used for single nucleotide polymorphism (SNP) genotyping. Out of 231 SNPs identified in those 15 ABC transporter genes, 89 and 75 of them were specific to the SUS or LOE populations, respectively. A few of the SNPs identified may affect gene expression, protein function, substrate specificity or resistance development and may be useful for transporter inhibitor/anthelmintic drug design, or in order to anticipate resistance development.

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“…One obvious set of studies would test both adult and PZQ-refractory juvenile worms for changes in PZQ potency when it is combined with inhibitors of Pgp or other multidrug transporters. Indeed, these types of experiments have shown that that co-administration of MDR reversing agents (eg, Pgp inhibitors such as verapamil) can increase susceptibility to macrocyclic lactones in a variety of drug-resistant and -sensitive nematodes [107,108,109,110,111,112]. RNA interference experiments in schistosomes to test the effects of knockdown of these transporters on PZQ sensitivity could be used to confirm the pharmacological studies, but with greater specificity.…”

Section: Conclusion and Prospects For Future Researchmentioning

confidence: 99%

ABC multidrug transporters in schistosomes and other parasitic flatworms

Greenberg

2013

Parasitology International

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Schistosomiasis, a neglected tropical disease affecting hundreds of millions, is caused by parasitic flatworms of the genus Schistosoma. Treatment and control of schistosomiasis relies almost exclusively on a single drug, praziquantel (PZQ), a dangerous situation for a disease of this magnitude. Though PZQ is highly effective overall, it has drawbacks, and reports of worms showing PZQ resistance, either induced in the laboratory or isolated from the field, are disconcerting. Multidrug transporters underlie multidrug resistance (MDR), a phenomenon in which resistance to a single drug is accompanied by unexpected cross-resistance to several structurally unrelated compounds. Some of the best studied multidrug transporters are members of the ancient and very large ATP-binding cassette (ABC) superfamily of efflux transporters. ABC multidrug transporters such as P-glycoprotein (Pgp; ABCB1) are also associated with drug resistance in parasites, including helminths such as schistosomes. In addition to their association with drug resistance, however, ABC transporters also function in a wide variety of physiological processes in metazoans. In this review, we examine recent studies that help define the role of schistosome ABC transporters in regulating drug susceptibility, and in normal schistosome physiology, including reproduction and excretory activity. We postulate that schistosome ABC transporters could be useful targets for compounds that enhance the effectiveness of current therapeutics as well as for agents that act as antischistosomals on their own.

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The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

Cited by 19 publications

References 60 publications

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Polymorphism in ABC transporter genes of Dirofilaria immitis

ABC multidrug transporters in schistosomes and other parasitic flatworms

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