Development of small molecule inhibitors of a gut bacterial metabolic toxin

New therapies are needed to address the related worldwide epidemics of obesity and type 2 diabetes (T2D). The success of the peptidic glucagon-like peptide-1 (GLP-1) receptor agonists semaglutide and tirzepatide has revealed that there is a massive market for effective obesity and T2D treatments. However, these drugs have notable side effects, including nausea and vomiting. Moreover, because they are peptides, they are expensive and labor-intensive to produce. There is an unmet need for effective small molecule treatments for T2D and obesity. Such drugs would increase access to care for metabolic syndrome to underserved populations worldwide. One potential source of such anti-diabetic small molecules is bariatric surgery. This procedure is a highly effective treatment for obesity and T2D that results in significant and sustained weight loss and T2D resolution. Biochemical changes have been hypothesized to underlie the rapid nature of the T2D resolution after surgery, which occurs only hours post-surgery and is decoupled from weight loss. In new work, we have found that a bacterially produced bile acid whose levels are significantly decreased in feces following bariatric surgery substantially impairs glucose tolerance and reduces insulin sensitivity in vivo. We have also identified two selective inhibitors of bacterial production of this toxic metabolite. These compounds ameliorate glucose intolerance in high fat diet-fed mice. However, these inhibitors are carcinogens at high concentrations. We propose to develop and validate high-throughput assays and pursue medicinal chemistry strategies to develop synthetic, non-toxic versions of the inhibitors as novel treatments for T2D.