Next-Generation Antibiotics

Finding new antibiotics to treat infections caused by Pseudomonas aeruginosa is a compelling medical need, since the inherently antibiotic resistant nature of the bacteria is being enhanced by the increasing appearance of strains resistant to all currently-marketed antibiotics. Lipopolysaccharide (LPS) is a required and constitutive component of the outer membrane of Gram-negative bacteria, including Ps. aeruginosa, Escherichia coli, Salmonella and Shigella species, which contributes significantly to antibiotic resistance. WaaP is a kinase encoded by these organisms and is required for complete synthesis of LPS. Knock-out mutations in the waaP gene are lethal in Ps. aeruginosa thus making inhibition of WaaP a useful target for the development of new antibiotics. The goal of the proposed project is to find small molecule inhibitors of WaaP that will be developed into a new class of narrow-spectrum antibiotics especially targeted to Ps. aeruginosa. The research proposed will support high-throughput screening of a 100,000+ compound library and numerous follow-up assays in order to identify compounds with pharmaceutical properties suitable to serve as templates for antibiotic development. The proposal also describes intensive medicinal chemistry efforts and biological and early toxicological evaluations of newly synthesized drug candidates.