Exploring the potential to improve azole efficacy against Trypanosoma cruzi by targeting glutamine metabolism

探索通过靶向谷氨酰胺代谢提高唑类药物对抗克氏锥虫功效的潜力

基本信息

批准号：
10355041
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
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-27 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355041
关键词：
Achievement Aftercare Animal Model Antifungal Agents Azoles Biological Assay Biological Availability Carbon Cardiomyopathies Cells Cessation of life Chagas Disease Characteristics Chemicals Chronic Clinical Trials Collection Coupled Development Environment Exposure to Failure Fingerprint Future Gastrointestinal Motility Gastrointestinal tract structure Glutamate Dehydrogenase Glutamine Goals Growth Human Individual Infection Lanosterol Large Intestine Life Link Lytic Phase Mammalian Cell Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Myocarditis Outcome Parasites Parasitic infection Pathway interactions Patients Pharmaceutical Preparations Play Population Predisposition Probability Proliferating Property Refractory Regimen Risk Factors Role Sterility Sterol Biosynthesis Pathway Sterols Testing Tissues Toxic effect Treatment Protocols Treatment outcome Trypanocidal Agents Trypanosoma cruzi base chronic infection comparative improved in vitro activity in vivo inhibitor/antagonist interest metabolomics motility disorder mutant novel pathogen posaconazole public health relevance response screening small molecule small molecule libraries tool

项目摘要

PROJECT SUMMARY Chronic infections with the Chagas disease parasite, Trypanosoma cruzi, are notoriously difficult to treat with the current drug regimens. The mechanism(s) underlying recalcitrant T. cruzi infection are unknown, but this remains one of the most pressing problems in the field. Of the potential explanations for drug failure, the role that heterogeneous metabolic environments might play in drug susceptibility in T. cruzi, has not been explored. Recently, we discovered a novel link between glutamine metabolism and the trypanocidal action of a group of azole compounds that target sterol biosynthesis in T. cruzi amastigotes. We find that under conditions of limiting glutamine availability, intracellular amastigotes survive exposure to lethal concentrations of azoles, including posaconazole, a drug that failed to clear T. cruzi infection from chronically-infected Chagas patients in clinical trials. Given evidence that glutamine levels are lowest in the region of the gastrointestinal tract that these parasites are known to persist and recrudesce following azole treatment, our novel findings may have important implications for the failure of posaconazole to clear parasite infection in mice and chronic Chagas patients. The goals of this exploratory R21 proposal are to define the mechanism(s) by which access to exogenous glutamine modulates azole-dependent killing of intracellular T. cruzi amastigotes and to identify compounds in small molecule library screens that specifically ablate parasite protection from azoles under conditions of glutamine restriction in culture. Results from this study have the potential to reveal auxiliary glutamine-sensitive pathways in the parasite that can be targeted to potentiate the efficacy of azoles in low glutamine settings as well a set of compounds that will serve as powerful tools for future functional studies.

项目摘要众所周知，Crypanosoma cruzi的慢性感染很难用当前的药物方案。顽固的T. cruzi感染的基本机制尚不清楚，但这仍然存在该领域最紧迫的问题之一。潜在的药物衰竭解释，这是尚未探讨异质的代谢环境在T. Cruzi的药物敏感性中可能发挥作用。最近，我们发现了谷氨酰胺代谢与一组锥虫作用之间的新颖联系千唑化合物靶向Cruzi杂种中的固醇生物合成。我们发现在限制条件下麸 popaconazole，一种未能从临床中慢性感染的chagas患者清除t. cruzi感染的药物试验。有证据表明谷氨酰胺水平在胃肠道区域中最低众所周知，寄生虫会在Azole治疗后持续并饲养，我们的新发现可能具有重要的对寄生虫未能清除小鼠和慢性Chagas患者清除寄生虫感染的意义。这该探索性R21提案的目标是定义获得外源谷氨酰胺的机制调节偶氮依赖性杀死细胞内T. cruzi amastigotes，并鉴定小的化合物在谷氨酰胺条件下，分子库的筛选特别是在偶氮中烧蚀寄生虫保护的筛选文化的限制。这项研究的结果有可能揭示辅助谷氨酰胺敏感的途径在寄生虫中，可以旨在增强硫唑在低谷氨酰胺环境中的功效以及一组将作为未来功能研究的强大工具的化合物。