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.
