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

项目摘要/摘要 帕金森氏病(PD)是一种由于多巴胺缺乏而导致的毁灭性的神经系统疾病 神经传递，目前尚无治愈方法。然而，有可用的药物治疗来治疗 改善症状。用于帕金森病治疗的一类药物是儿茶酚-O- 甲基转移酶抑制剂(COMT-I)。然而，已知COMT-I可引起多个 PD患者的不良事件，包括罕见但致命的肝毒性。我们的实验室已经证明 一种COMT-I，entacapone，被多种肠道细菌广泛地进行硝化还原。另外， 其他研究表明，恩塔卡彭和托卡彭可通过复杂的肠道进行不同的硝化还原 细菌群落在体外。先前的研究也表明COMT-I与 肠道共生丰度的变化，以及恩塔卡彭作为反共生的作用 毒品。这项提案提出了一项计划，以了解肠道微生物组如何调节COMT-I 通过代谢转化影响药物功能和毒性的疗效和毒性 微生物群的破坏。我在一个普通的肠道中发现了具有活性的COMT-I硝基还原酶 共生菌的研究表明，甲苯酚的硝化还原导致损失 体外和体外的药物疗效，并开始表征细菌COMT-I之间的联系 硝化还原和抗菌活性。在目标1中，我将确定细菌的新陈代谢 影响COMT-I PK/PD和寄主毒性，以及硝酸还原酶在体外如何存在 复杂的人类细菌群落会影响药物代谢和代谢物的产生。在AIM 2、我将深入研究导致COMT-I对细菌的毒性的方面，细菌 硝化还原在这种毒性中起着作用，以及可变的COMT-I代谢如何影响复合体 细菌群落结构。如果成功，我的研究将揭开一个以前隐藏的方面 关于COMT-I的有效性、毒性和微生物群破坏如何受到广泛的 细菌硝化还原。该项目还将为我提供关键的研究培训机会 关于药理学、分析化学、微生物学和生物化学的研究。 此外，我将接触到许多专业培训机会，以提高我的技能 例如导师、教学、科学写作和科学演示等领域。在支持下 我的论文导师安德鲁·古德曼博士正在进行这个项目和这些培训计划，请访问 耶鲁大学将允许我成长为一名独立的研究员。

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.