Design and Synthesis of Novel LpxC Inhibitors to Impede Outer Membrane Formation in Gram-Negative Bacteria

Abstract

The increasing global incidence of antibiotic-resistant Gram-negative bacteria necessitates the discovery of new treatment mechanisms to combat such untreatable and deadly infections. One promising target is LpxC, a highly conserved Gram-negative enzyme which performs a crucial step in the lipid A biosynthetic pathway. Lipid A serves as the anchor for lipopolysaccharides on the Gram-negative outer membrane and is essential to the structural integrity and viability of the bacterium. The LpxC active site is comprised of a zinc ion, a polar region, and a hydrophobic passage. A library of analogs with varying hydrophobic tails similar in structure to the natural substrate were designed and synthesized with the goal of optimizing binding within the active site. Two new analogs (DP-001 and DP-002) were added to the existing LpxC inhibitor library which contain a phenyl propargyl ethertail as a hydrophobic moiety. The phenyl propargyl ether tail was synthesized and a new approach was developed to achieve hydroxamic acid conversion. Both DP-001 and DP-002 will be tested alongside the rest of the Peterson library against various strains of Gram-negative and Gram-positive bacteria for antimicrobial activity.