Bacterial metabolism of catechol-O-methyltransferase inhibitors alters drug efficacy and toxicity

儿茶酚-O-甲基转移酶抑制剂的细菌代谢改变药物疗效和毒性

• 批准号: 10606184
• 负责人: Andrew Albert Verdegaal
• 金额: $ 3.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-10 至 2025-01-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606184
• 关键词: 16S ribosomal RNA sequencing; Adverse event; Affect; American; Analytical Chemistry; Anti-Bacterial Agents; Antibiotics; Area; Bacteria; Bacteroides thetaiotaomicron; Biochemistry; Biological Assay; Biological Availability; Brain; Catechol O-Methyltransferase; Communities; Complex; Data; Disease; Dopamine; Drug Combinations; Drug Side Effects; Drug toxicity; Drug usage; Educational process of instructing; Enzymes; Exhibits; Exposure to; Family; Genetic; Genetic Transcription; Gnotobiotic; Hepatotoxicity; Human; Human Microbiome; In Vitro; Individual Differences; Intervention; Levodopa; Link; Mass Spectrum Analysis; Mediating; Mentorship; Metabolic; Metabolism; Metagenomics; Microbiology; Motor Manifestations; Mus; Nervous System; Neurologic; Neurologic Symptoms; Neurotransmitters; Nitroreductases; Oral; Parkinson Disease; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Production; Quality of life; Reporting; Research; Research Personnel; Research Training; Structure; Testing; Tissues; Toxic effect; Training; Variant; Writing; bacterial community; bacterial metabolism; dopaminergic neuron; drug efficacy; drug metabolism; entacapone; experimental study; gastrointestinal; gut microbes; gut microbiome; gut microbiota; improved; in vivo; inhibitor; inhibitor therapy; insight; liquid chromatography mass spectrometry; microbial; microbiome; model organism; neurotransmission; reduce symptoms; side effect; skills; tolcapone; training opportunity

Project Summary/ Abstract Parkinson’s disease (PD) is a devastating neurological illness due to a deficit of dopamine neurotransmission with no known cure. Nevertheless, there are available drug treatments for ameliorating symptoms. One class of drugs used in PD therapy are the Catechol-O- Methyltransferase inhibitors (COMT-I’s). However, COMT-I’s are known to cause multiple adverse events in PD patients, including a rare but fatal hepatotoxicity. Our lab has shown that one COMT-I, entacapone, is widely nitroreduced by a multiple gut bacterial species. Additionally, other studies have shown variable nitroreduction of entacapone and tolcapone by complex gut bacterial communities in vitro. Previous studies have also shown that COMT-I’s are linked with changes in gut commensal abundances, as well as entacapone acting as an anti-commensal drug. This proposal presents a plan to understand how the gut microbiome modulates COMT-I efficacy and toxicity through metabolic transformations which impact drug function and microbiome disruption. I have identified active COMT-I nitroreductases in a common gut commensal, Bacteroides thetaiotaomicron, shown that nitroreduction of tolcapone leads to loss of drug efficacy in vitro and ex vivo, and began to characterize a link between bacterial COMT-I nitroreduction and anti-bacterial activity. In Aim 1, I will determine how bacterial metabolism affects COMT-I PK/PD and host toxicity, as well as how nitroreductase presence in in vitro complex human bacterial communities affects drug metabolism and metabolite production. In Aim 2, I will delve into the aspects which cause COMT-I’s to be toxic towards bacteria, how bacterial nitroreduction plays a role in this toxicity, and how variable COMT-I metabolism affects complex bacterial community structure. If successful, my research will uncover a previously hidden aspect of how COMT-I efficacy, toxicity, and microbiome disruption can be influenced by a widespread bacterial nitroreduction. This project will also provide me key research training opportunities regarding studies using pharmacology, analytical chemistry, microbiology, and biochemistry. Furthermore, I will be exposed to many professional training opportunities to improve my skills in areas such as mentorship, teaching, scientific writing, and scientific presentation. With the support of my thesis advisor, Dr. Andrew Goodman, pursuing this project and these training plans here at Yale will allow me to grow as an independent researcher.

项目摘要/摘要 帕金森氏病（PD）是一种毁灭性的神经系统疾病，由于多巴胺不足 神经传递没有已知的治疗方法。然而，有可用的药物治疗 改善症状。 PD治疗中使用的一类药物是Catechol-O- 甲基转移酶抑制剂（COMT-I）。但是，已知COMT-I会导致多个 PD患者的不良事件，包括罕见但致命的肝毒性。我们的实验室表明 一种comt-i，intacapone，被多种肠道细菌广泛硝化。此外， 其他研究表明，复杂的肠道对Entacapone和Tolcapone的硝化作用可变 细菌社区体外。先前的研究还表明，COMT-I与 肠道元素丰度的变化以及肠道的变化 药品。该提案提出了一个计划，以了解肠道微生物组如何调节COMT-I 通过影响药物功能和的代谢转化的功效和毒性 微生物组中断。我已经确定了普通肠道中的活性COMT-I硝酸还原酶 共生菌菌的thetaiotaomicron，表明硝化作用导致损失 体外和离体的药物效率，并开始表征细菌comt-i之间的联系 硝化作用和抗菌活性。在AIM 1中，我将确定细菌代谢如何 影响COMT-I PK/PD和宿主毒性，以及硝酸还原酶在体外的存在 复杂的人类细菌群落会影响药物代谢和代谢产物的产生。目标 2，我将深入研究导致COMT-I对细菌有毒的方面，细菌如何 硝化作用在这种毒性中起作用，以及COMT-I代谢的可变影响如何影响复合物 细菌社区结构。如果成功的话，我的研究将揭示以前隐藏的方面 IMT-I效率，毒性和微生物组的破坏如何受到宽度的影响 细菌硝化作用。该项目还将为我提供重要的研究培训机会 考虑使用药物，分析化学，微生物学和生物化学的研究。 此外，我将获得许多专业培训机会，以提高我的技能 诸如精神训练，教学，科学写作和科学演示等领域。在支持下 我的论文顾问安德鲁·古德曼（Andrew Goodman）博士在此处追求这个项目和这些培训计划 耶鲁大学将使我成为一名独立研究人员。