Redesign of biotin carboxylase inhibitors

As the frequency of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial development. Amino-oxazole inhibits biotin carboxylase (BC) activity in Gram-negative organisms. In collaboration with Grover Waldrop, we redesigned previously identified lead inhibitors of BC to expand the spectrum of bacteria sensitive to the amino-oxazole derivatives by including Gram-positive species. Structural insights into drug-BC interactions will be exploited to increase the potency of amino-oxazole inhibitors towards both Gram-negative as well as Gram-positive species.