The human gut microbiome exerts a profound effect on our health via a complex network of metabolic feedback. An important component of this system is the chemical transformation of xenobiotics, including pharmaceuticals and dietary nutrients. Our lab has shown that choline, an important nutrient, is transformed into trimethylamine (TMA) by gut bacteria containing the choline utilization (cut) gene cluster. TMA has been associated with several pathologies, including cardiovascular disease. Although recent evidence suggests that small molecule drugs may interact with the microbiome, their potential for targeting microbial pathways has not been fully utilized. Here, we describe a target-agnostic, phenotypic high-throughput screen that has identified approved drugs that interfere with TMA generation from choline by gut bacteria. After screening ~10,000 compounds, we found two drugs that inhibit TMA production by the prominent choline-utilizing gut bacteria, Escherichia coli and Clostridium sporogenes. These drugs exhibit IC50 values of ~ 1 μM against TMA generation, while not affecting bacterial growth. Future work will focus on identifying the molecular target(s) of these compounds and their effects in defined and complex microbial communities in vivo. Overall, we show that phenotypic high-throughput screening is a powerful tool for uncovering compounds that target gut microbial metabolic activities, and that known drugs can potentially be repurposed for modulation of the human microbiome

Growth-based phenotypic high throughput screening (HTS) platform to discover drugs that inhibits the proatherogenic trimethylamine (TMA) pathway in the human gut microbiome

256th National Meeting (2018)

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