Mani Thangadurai, Bourguinat Catherine, Prichard Roger K
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Int J Parasitol Drugs Drug Resist. 2017 Aug;7(2):227-235. doi: 10.1016/j.ijpddr.2017.04.004. Epub 2017 Apr 29.
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.
犬恶丝虫是一种丝状线虫，可导致犬、猫感染恶丝虫病，偶尔也会感染人类。预防该病主要是在蚊虫传播季节每月使用大环内酯类体内外寄生虫杀虫剂。最近，已证实犬恶丝虫对大环内酯类产生了抗性，因此，需要寻找新的驱虫药类别。与线虫对大环内酯类抗性相关的一种机制可能是ATP结合盒（ABC）转运蛋白在降低受体部位药物浓度方面的作用。ABC转运蛋白主要来自B、C和G亚家族，可能通过将药物主动排出细胞而导致多药耐药（MDR）。ABC转运蛋白的基因产物因此可能成为通过抑制药物转运来调节药物敏感性的药物靶点。ABC转运蛋白被认为参与了对寄生虫至关重要的多种生理功能，如甾醇转运，因此也可能成为本身可作为驱虫药的药物靶点。了解线虫寄生虫中这些ABC转运蛋白基因的多态性可为药物设计过程提供有用信息。我们通过比较基因组学方法在犬恶丝虫中鉴定了来自A、B、C和G亚家族的15个ABC转运蛋白基因，并对其多态性进行了分析。来自四个大环内酯类敏感（SUS）和四个药效丧失（LOE）混合群体的全基因组测序数据用于单核苷酸多态性（SNP）基因分型。在这15个ABC转运蛋白基因中鉴定出的231个SNP中，分别有89个和75个特定于SUS或LOE群体。鉴定出的一些SNP可能影响基因表达、蛋白质功能、底物特异性或抗性发展，可能有助于转运蛋白抑制剂/驱虫药设计，或用于预测抗性发展。
