Discovery of Novel Small Molecule Inhibitors of Bacterial Pyruvate Carboxylase

Abstract

Staphylococcus aureus and Listeria monocytogenes are pathogenic bacteria that can cause serious infections for immunocompromised individuals1, 2. Bacterial metabolism has been linked to pathogenicity and, in particular, the metabolic enzyme pyruvate carboxylase (PC) has been shown to be an important contributor to L. monocytogenes virulence1, 2. Small molecules that could inhibit bacterial PC activity would better reveal the role of this enzyme in a wide range of bacterial infections and could have the potential to be developed into antimicrobial agents. However, there are currently no known specific or potent small molecule inhibitors of PC activity3. We aim to find, develop, and characterize novel small molecule inhibitors of PC that will aid in understanding the structure, mechanism, and regulation of this enzyme. PC catalyzes the conversion of pyruvate to oxaloacetate (OAA) and a novel fixed‐time assay has been developed to detect OAA with a diazonium salt, Fast Violet B (FVB). The validated assay has been used to screen specific subsets of rationally designed inhibitors as well as compounds in an unbiased high‐throughput screen. Using both approaches, we have discovered novel small molecule inhibitors of bacterial PC that have the potential to be developed into valuable research tools and future antimicrobial agents.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.