Medicinal Chemistry in the Design and Synthesis of New Antibiotics Targeting Bacterial Enzymes

The crisis of rising bacterial resistance underlines the need for the discovery of new antibiotics, particularly with new mechanisms of action. Our research is focused on discovering new antibiotics through development of scaffolds that selectively interact with essential bacterial di-nuclear enzymes, and we are targeting three separate di-zinc-metallo-enzymes that are unique to bacteria and play key roles in their growth and development, including DapE, AiiA, and NDM-1. DapE is involved in biosynthesis of lysine and meso-diaminopimelic acid, essential precursors in the production of bacterial cell walls, whereas AiiA is a di-Zn-dependent lactonase involved in bacterial cell-cell communication. NDM-1 is a di-metallo-beta-lactamase capable of deactivating the most commonly administered antibiotics, gaining international attention as a clinically-relevant pharmaceutical target. Efforts in our lab to selectively target di-metal specific catalytic sites in metallo-proteins have led to the discovery of compounds that target all three of these enzymes, including compounds that are the most potent inhibitors of NDM-1 to date. Medicinal chemistry design, synthesis, docking and preliminary biological results will be presented.