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.

项目概要 犬钩虫引起皮肤幼虫移行症和嗜酸性粒细胞性肠炎 人类。这些人类疾病之所以无法消除，是因为 寄生虫持续存在于犬科宿主体内。犬放线菌多重耐药菌株 现在在美国流传。此外，特定的生命周期阶段（组织- 即使分离株被认为是“药物”，居住幼虫也能耐受驱虫药。 易受影响的。” 我们的假设是，A. caninum 通过渗透性逃避药物治疗 糖蛋白（P-糖蛋白）流出驱虫剂并防止它们结合 靶受体。在此应用中，我们建议 1) 识别频谱 通过 A. caninum 中的 P-糖蛋白抑制增强驱虫药，2) 记录 针对每种药物类别表达的 Pgps 库，3) 绘制精确的组织图 其中 Pgps 被表达，4) 表征 Aca-Pgp-11 的药理学特征， 5)凭经验确定线虫P-糖蛋白特定位点的区域 可能会被利用。我们的结果将为未来测试以下假设的研究提供信息 线虫特异性 P-糖蛋白抑制剂可用于恢复多种药物的功效 现有驱虫药并克服耐药性钩虫。

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.