Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH

Despite the widespread emergence of multidrug-resistant nosocomial Gram-negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram-negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug-resistant Gram-negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese-containing UDP-2,3-diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram-negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH (KpLpxH), here we report the development and structural validation of the first-in-class sulfonyl piperazine LpxH inhibitors, JH-LPH-45 (8) and JH-LPH-50 (13), that achieve chelation of the active site dimanganese cluster of KpLpxH. The chelation of the dimanganese cluster significantly improves the potency of JH-LPH-45 (8) and JH-LPH-50 (13). We expect that further optimization of these proof-of-concept dimanganese-chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug-resistant Gram-negative pathogens.