Exploring metabolic resistance to small molecule inhibitors in Trypanosoma cruzi

探索克氏锥虫对小分子抑制剂的代谢耐药性

• 批准号: 9808666
• 负责人: BARBARA A BURLEIGH
• 金额: $ 23.93万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808666
• 关键词: Address; Adipose tissue; Anabolism; Animal Model; Biochemical; Biological; Biological Assay; CRISPR/Cas technology; Carbon; Cardiomyopathies; Case Study; Cell Culture Techniques; Cell physiology; Cells; Chagas Disease; Characteristics; Chemotherapy-Oncologic Procedure; Chronic; Citric Acid Cycle; Clinical Trials; Collection; Coupled; Data; Development; Disease; Environment; Ergosterol; Exhibits; Failure; Follow-Up Studies; Future; Genes; Glutamate Dehydrogenase; Glutamine; Goals; Growth; Growth Inhibitors; Heterogeneity; Human; In Vitro; Industry; Infection; Investigation; Isocitrate Dehydrogenase; Ketoconazole; Lead; Life; Light; Link; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Molecular Genetics; Mus; Nature; Parasite Control; Parasites; Parasitic infection; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Refractory; Resistance; Risk; Role; Site; Smooth Muscle; Source; Testing; Tissues; Treatment Failure; Treatment Protocols; Trypanocidal Agents; Trypanosoma cruzi; Tumor stage; Vascular blood supply; carboxylation; cell type; chemotherapeutic agent; chronic infection; cohort; congenital infection; drug efficacy; flexibility; gastrointestinal; genetic resistance; high throughput screening; in vivo; inhibitor/antagonist; metabolic abnormality assessment; metabolomics; mutant; nanomolar; neoplastic cell; next generation; novel; open source; pathogen; posaconazole; response; screening; small molecule inhibitor; targeted agent; tool

Project Summary Chronic infections with the protozoan parasite and causative agent of human Chagas disease, Trypanosoma cruzi, are notoriously challenging to treat. The available drugs often fail to achieve sterilizing cure under the current treatment regimens. Ergosterol biosynthesis inhibitors (EBIs) also failed to clear parasites from chronic patients in recent clinical trials. These findings, coupled with results from animal models showing selective survival of T. cruzi in certain tissues after EBI treatment, raise the possibility that characteristics of the local tissue environment impact susceptibility of intracellular parasites to trypanocidal drugs. In the cancer field, it is well-established that differences in the metabolic state of tumor cells, due to heterogeneity of cell populations and their environments, can lead to `metabolic resistance' and treatment failure. Because T. cruzi colonizes diverse tissues in the mammalian host, each with its own unique metabolic signature, we hypothesize that comparable mechanisms of metabolic resistance to anti-trypanosomal drugs may contribute to failure to achieve parasitological cure in chronic T. cruzi infection. Consistent with this idea, preliminary studies show that a single change in the composition of the cell culture medium protects intracellular T. cruzi amastigotes from the lethal effects of EBIs. The goals of this proposed study are to determine the role of glutamine metabolism in sensitizing T. cruzi amastigotes to EBIs using a combination of molecular genetic and biochemical approaches (Aim1) and to determine the broader impact of metabolic environment on the efficacy of the next generation of candidate anti-trypanosomals by re-screening the ChagasBox collection of T. cruzi growth inhibitors under diverse conditions (Aim 2). As a case study for metabolic resistance, the proposed study addresses a critical gap in our understanding of how diverse cellular and metabolic environments, such as those encountered by T. cruzi in vivo, impact the ability to effectively eliminate this pathogen from infected hosts, a key current challenge in the treatment of Chagas disease.

项目摘要 慢性感染原生动物寄生虫和人类恰加斯病病原体锥虫 众所周知，治疗具有挑战性。现有的药物往往无法在 目前的治疗方案。麦角固醇生物合成抑制剂（EBI）也未能清除慢性寄生虫， 在最近的临床试验中。这些发现，再加上动物模型的结果显示，选择性 T的生存。EBI治疗后某些组织中的cruzi，提高了局部特征的可能性， 组织环境影响细胞内寄生虫对杀锥虫药物的敏感性。在癌症领域， 已经确定，由于细胞群的异质性，肿瘤细胞的代谢状态存在差异， 以及他们的环境，可能导致“代谢抵抗”和治疗失败。因为T.克鲁兹殖民 哺乳动物宿主中的不同组织，每个组织都有自己独特的代谢特征，我们假设， 对抗锥虫药物的代谢抗性的类似机制可能导致 实现慢性T.克氏感染与这一观点相一致的是，初步研究表明， 细胞培养基组成的单一变化可以保护细胞内T细胞。克氏无鞭毛体 不受EBI的致命影响这项研究的目的是确定谷氨酰胺的作用 代谢在致敏T.克氏无鞭毛体到EBI使用分子遗传学和 生物化学方法（Aim1），并确定代谢环境对疗效的更广泛影响 通过重新筛选T. cruzi 在不同条件下的生长抑制剂（目标2）。作为代谢抵抗的案例研究， 这项研究解决了我们对不同细胞和代谢环境的理解中的一个关键空白， 与T. cruzi在体内的影响，能够有效地消除这种病原体从感染 这是目前治疗恰加斯病的一个关键挑战。