Microbiome Targeted Drugs to Improve NSAID Outcomes

DESCRIPTION provided by applicant This project advances a new therapeutic paradigm of selective pharmacological control of microbiome function to improve human health The use of non steroidal anti inflammatory drugs NSAIDs is associated with intestinal ulceration inflammation and bleeding that result in reduced quality of life hospitalization and even death These NSAID induced side effects are triggered by an enzyme in the intestinal microbiome the bacterial glucuronidase bGUS enzyme whose activity results in the production of toxic NSAID by products that damage the intestinal lumen This proposal aims to synthesize and characterize new drug candidates that selectively inhibit bacterial bGUS to be developed as therapeutic adjuncts to improve the benefit to risk outcomes associated with NSAID therapy We previously reported the discovery of the first class of compounds that selectively blocks bacterial bGUS without exhibiting antibiotic activity As a proof of concept a prototype bGUS inhibitor Inh was shown to alleviate all measures of enteropathy in mice induced by three NSAIDs diclofenac indomethacin and ketoprofen We have since identified another non proprietary selective and non toxic bacterial bGUS inhibitor Inh that is andgt fold more potent than Inh Inh is a promising scaffold for hit to lead chemistry and lead optimization However Inh undergoes extensive first pass metabolism and intestinal absorption following oral dosing We propose to rationally design and synthesize novel analogues that retain the potency selectivity and non antibiotic activity of Inh while exhibiting low intrinsic metabolim and oral bioavailability The proposed analogues are expected to be more efficacious in the GI tract and less likely to produce systemic side effects This project will employ proven drug discovery approaches to enable the identification of a promising novel lead series that can be further optimize into a clinical candidate Our research strategy lays the groundwork for the discovery of the first microbiome targeted human therapeutic that is Effective in reducing the risks of lower GI damage from NSAID use not harmful to beneficial intestinal microbes and safe for the human host PUBLIC HEALTH RELEVANCE The use of non steroidal anti inflammatory drugs NSAIDs is associated with clinically important side effects in the lower gastrointestinal GI tract such as ulceration inflammation and bleeding These side effects are caused by an enteric microbial enzyme bacterial glucuronidase in the intestinal microbiome whose activity results in the production of toxic NSAID by products that damage the small bowel and colon This project aims to synthesize and characterize novel non antibiotic drug candidates that selectively inhibit this microbial enzyme to prevent NSAID induced lower GI damage without harming the beneficial bacteria in the intestinal microbiome