Infectious disease

In silico, in vitro and mouse studies identified an oxazolidinone-based LpxC inhibitor that could help treat Gram-negative bacterial infections. In silico screening of analogs of an indazole-based LpxC inhibitor, followed by chemical synthesis, in vitro assays and optimization of the resulting hits identified an oxazolidinone compound that inhibited the growth of Pseudomonas aeruginosa, E. coli and Klebsiella pneumoniae strains with minimum inhibitory concentration (MIC) values of 0.5, 0.125 and 1 μg/mL, respectively. In a mouse model of neutropenia-associated P. aeruginosa thigh infection, the compound decreased bacterial load in the thigh compared with no treatment. In a mouse model of K. pneumoniae lung infection, the compound plus the generic antibiotic vancomycin decreased bacterial load in the lung compared with either agent alone. Crystallography analysis of P. aeruginosa LpxC complexed with the compound identified binding interactions between the compound and six amino acids in the LpxC active site, suggesting LpxC as the compound’s probable target. Next steps by Novartis AG could include testing the compound in additional animal models of bacterial infection.

A2A Pharmaceuticals LLC has the LpxC inhibitor AA-001 in preclinical testing for Gram-negative bacterial infection...