The Total Synthesis and Biological Evaluation of Drimane Sesquiterpenoids

Project Summary: Antimicrobial resistance (AMR) is a grave public health concern resulting in millions of infections in the United States each year. These resistant infections place a high financial burden on patients and the healthcare system. At the center of these resistant infections are six opportunistic “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), which cause over half of all healthcare-associated infections. As such, there is a dire societal need to develop novel antimicrobial compounds with unique mechanisms of action (MOA) to combat these ubiquitous pathogens. Targeting a novel MOA decreases the likelihood of cross-resistance. To identify new compounds with potent biological activity and potentially a new MOA, we turn to natural products. Natural products are secondary metabolites that have been used for their medicinal properties thousands of years. Today, upwards of one-third of all FDA-approved drugs come from natural products. Taken together, natural product synthesis represents a valuable starting point for the discovery of antimicrobial compounds with a novel mechanism of action. The drimane sesquiterpenoid family of natural products has potent activity against a wide range of antimicrobial pathogens including Pseudomonas aeruginosa and Staphylococcus aureus. Drimane sesquiterpenoids are structurally distinct from traditional antibiotics, suggesting they may have a novel MOA. However, their scarce supply in nature limits our understanding of their biological activity. This application proposes the total synthesis of over 15 drimane sesquiterpenoids from a single precursor, all with underexplored or unreported biological activity. Additionally, we will use this diverted synthetic platform to conduct a hypothesis- driven analog campaign to yield unnatural analogs with superior biological properties. With this library of synthetic compounds, we will perform a series of biological assays including resistance selection to elucidate the mechanism of action of these drimane sesquiterpenoids. This interdisciplinary proposal will propel our understanding of these potent antimicrobial natural products and potentially identify a novel target for further antibiotic drug development.