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

UDP-3- O -( R -3-hydroxymyristoyl)- N -acetylglucosamine deacetylase (LpxC) is a promising drug target in Gram-negative bacteria. Previously, we described a correlation between the residence time of inhibitors on Pseudomonas aeruginosa LpxC ( pa LpxC) and the post-antibiotic effect (PAE) caused by the inhibitors on the growth of P. aeruginosa . Given that drugs with prolonged activity following compound removal may have advantages in dosing regimens, we have explored the structure-kinetic relationship for pa LpxC inhibition by analogues of the pyridone methylsulfone PF5081090 ( 1 ) originally developed by Pfizer. Several analogues have longer residence times on pa LpxC than 1 (41 min) including PT913 , which has a residence time of 124 min. PT913 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 pa LpxC inhibitor residence time and the potential development of antibacterial agents that cause prolonged suppression of bacterial growth.