Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors.

UDP-3--(-3-hydroxymyristoyl)--acetylglucosamine deacetylase (LpxC) is a promising drug target in Gram-negative bacteria. Previously, we described a correlation between the residence time of inhibitors on LpxC (LpxC) and the post-antibiotic effect (PAE) caused by the inhibitors on the growth of . Given that drugs with prolonged activity following compound removal may have advantages in dosing regimens, we have explored the structure-kinetic relationship for LpxC inhibition by analogues of the pyridone methylsulfone () originally developed by Pfizer. Several analogues have longer residence times on LpxC than (41 min) including , which has a residence time of 124 min. also has a PAE of 4 h, extending the original correlation observed between residence time and PAE. Collectively, the studies provide a platform for the rational modulation of LpxC inhibitor residence time and the potential development of antibacterial agents that cause prolonged suppression of bacterial growth.