Discovery and Characterization of Borrelia burgdorferi c-di-AMP Phosphodiesterase Inhibitors

Abstract

Lyme disease is the most prevalent vector-borne illness in North America and Europe and is caused by the Gram-negative spirochete Borrelia burgdorferi (Bb). If caught early, a short course of antibiotics is effective in helping 85-90% of patients. However, there are many (10-15%) who suffer from persistent Bb infection which current antibiotics cannot treat. The Yang lab at IUSOM determined that the c-di-AMP phosphodiesterase DhhP is necessary for cell growth and virulence factor production. Because of this, DhhP has attracted our interest as a potential drug target. Our lab has recently completed a high-throughput screen (HTS) of 50,000 small molecules and found 4 compounds that have been confirmed to inhibit DhhP in vitro. Now, we aim to elucidate the mechanism(s) of inhibition as well as synthesize analogs of the hit molecules to obtain more potent and drug-like inhibitors. By the end of this project, we hope to have developed several small-molecule inhibitors of DhhP which can then be translated into clinically viable drugs.