We need new antibiotics. Emerging drug-resistant bacteria pose a serious threat to public health, and while medicinal chemists constantly battle to develop new antibiotics directed against these resistant strains, they still largely target the same molecular machinery as existing therapies. Histidine kinase-mediated two-component phospho-signaling pathways are particularly attractive, yet untapped targets for the development of new antibiotics because they play central—and often essential—roles in controlling the physiology of all bacterial cells. As a chemical biology laboratory, we take a multidisciplinary approach to antibiotic drug discovery by combining efforts in organic chemistry, biochemistry, and bacterial cell biology.
My laboratory endeavors to develop new antibacterial agents targeting histidine kinases, and we use the α-proteobacterium Caulobacter crescentus as our development platform. Histidine kinase-mediated signaling pathways are well conserved across bacterial species and are essential for virulence in many pathogenic bacterial strains, suggesting that discoveries in Caulobacter will open the door to potential new antibacterial strategies effective against a broad-spectrum of bacteria. Caulobacter contains essential histidine kinase signaling pathways that we target to assess whether pharmacological inhibition of these essential signaling pathways provides a new mechanism for antibacterial action. My laboratory’s current efforts focus on the design of a histidine kinase to incorporate strategically placed nucleophilic residues near the kinase active site. Concurrently, we are synthesizing small chemical molecules designed to react with these residues, and we are evaluating whether our molecules bind to the engineered kinase.