Overcoming multidrug-resistance in hookworms

克服钩虫的多重耐药性

• 批准号: 10593148
• 负责人: Matthew Brewer
• 金额: $ 22.95万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-16 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593148
• 关键词: ABCB1 gene; Accounting; Address; Adult; Amino Acids; Ancylostoma (genus); Ancylostoma caninum; Anthelmintics; Binding; Binding Sites; Biological Assay; CRISPR/Cas technology; Canis familiaris; Communicable Diseases; Cutaneous; Drug Targeting; Drug or chemical Tissue Distribution; Drug resistance; Exhibits; Future; Genes; Glycoproteins; Goals; Hookworms; Human; Kinetics; Knowledge; Larva; Larva Migrans; Life Cycle Stages; Mammals; Maps; Measures; Mediating; Messenger RNA; Mission; Modeling; Multi-Drug Resistance; Nematoda; Orthologous Gene; Outcome; Parasite resistance; Parasites; Permeability; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Predisposition; Property; Resistance; Site; System; Techniques; Testing; Tissues; United States; United States National Institutes of Health; Veterinarians; Zoonoses; disability-adjusted life years; enteritis; human disease; in vivo; inhibitor; lactogenesis; novel; pharmacologic; prevent; receptor; response; transmission process

Project Summary Ancylostoma caninum causes cutaneous larva migrans and eosinophilic enteritis in humans. The reason these human diseases cannot be eliminated is because the parasite persists in the canine reservoir host. Multi-drug resistant isolates of A. caninum are now circulating in the United States. In addition, specific life cycle stages (tissue- dwelling larvae) are tolerant of anthelmintics even when the isolate is considered “drug susceptible.” Our hypothesis is that A. caninum evades drug treatment with permeability glycoproteins (P-glycoproteins) that efflux anthelmintics and prevent them from binding target receptors. In this application we propose to 1) identify the spectrum of anthelmintics enhanced by P-glycoprotein inhibition in A. caninum, 2) record the repertoire of Pgps expressed in response to each drug class, 3) map the precise tissues where Pgps are expressed, 4) characterize the pharmacological profile of Aca-Pgp-11, and 5) empirically determine regions of specific sites of nematode P-glycoprotein that could be exploited. Our results will inform future studies testing the hypothesis that nematode-specific P-glycoprotein inhibitors can be used to restore efficacy of multiple existing anthelmintics and overcome drug resistant Ancylostoma.

项目摘要 犬钩虫引起皮肤幼虫移行症和嗜酸性肠炎， 人类这些人类疾病之所以不能被消除，是因为 寄生虫在犬类宿主体内持续存在。多药耐药菌株。caninum 现在在美国流传。此外，特定的生命周期阶段（组织- 寄生幼虫）对驱虫药耐受，即使该分离物被认为是“药物 易受影响。” 我们的假设是A.犬用渗透性逃避药物治疗 排出驱虫剂并阻止其结合的糖蛋白（P-糖蛋白） 靶受体。在本申请中，我们提出：1）识别 在A.犬，2）记录 响应于每种药物类别表达的Pgps的库，3）绘制精确的组织 其中表示Pgp，4）表征Pgp-11的药理学特征， 和5）凭经验确定线虫P-糖蛋白的特异性位点的区域， 可能被利用。我们的研究结果将为未来的研究提供信息， 线虫特异性P-糖蛋白抑制剂可用于恢复多种抗线虫药物的功效。 现有的驱虫药和克服耐药性钩虫。

项目成果

Repertoire of P-glycoprotein drug transporters in the zoonotic nematode Toxocara canis.

人畜共患毒素toxocara canis中P-糖蛋白药物转运蛋白的曲目。

• DOI: 10.1038/s41598-023-31556-1
• 发表时间: 2023-03-27
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Chelladurai, Jeba R. J. Jesudoss;Martin, Katy A.;Vardaxis, Pam;Reinemeyer, Craig;Vijayapalani, Paramasivan;Robertson, Alan P.;Brewer, Matthew T.
• 通讯作者: Brewer, Matthew T.