ci6004806_si_006.pdf (175.67 kB)
Escherichiacoli versus Pseudomonas aeruginosa Deacetylase LpxC Inhibitors Selectivity: Surface and Cavity-Depth-Based Analysis
journal contribution
posted on 2007-05-29, 00:00 authored by Rameshwar U. Kadam, Amol V. Shivange, Nilanjan RoyAlthough Escherichia coli and Pseudomonas aeruginosa LpxC share sequence and functional similarity, E.
coli LpxC inhibitiors are ineffective against P. aeruginosa LpxC. It was earlier speculated that inactivity of
the inhibitors is due to intrinsic resistance possibly mediated by efflux pumps. However, a recent study has
documented that the inactivity is due to failure of inhibitor(s) to inhibit the enzyme rather then intrinsic
resistance. In this study, we carried out a surface and cavity-depth-based analysis on homology models of
E. coli and P. aeruginosa LpxC to get some new insights into the ligand-binding features of these enzymes.
The surface analysis of the P. aeruginosa LpxC model suggested that the LpxC catalytic domain (where
inhibitors are supposed to bind) has several minor but potentially important structural differences as compared
to E. coli LpxC. Molecular docking studies which could distinguish between the reported receptor affinities
of the inhibitors additionally helped in the identification of key binding-site residues and interactions. These
differences can be exploited for designing broad-spectrum LpxC inhibitors against this target.