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

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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.