Toward the rational design of carbapenem uptake in Pseudomonas aeruginosa.

Chem Biol
Authors
Keywords
Abstract

Understanding how compound penetration occurs across the complex cell walls of Gram-negative bacteria is one of the greatest challenges in discovering new drugs to treat the infections they cause. A combination of next-generation transposon sequencing, computational metadynamics simulations (CMDS), and medicinal chemistry was used to define genetic and structural elements involved in facilitated carbapenem entry into Pseudomonas aeruginosa. Here we show for the first time that these compounds are taken up not only by the major outer membrane channel OccD1 (also called OprD or PA0958) but also by a closely related channel OccD3 (OpdP or PA4501). Transport-mediating molecular interactions predicted by CMDS for these channels were first confirmed genetically, then used to guide the design of carbapenem analogs with altered uptake properties. These results bring us closer to the rational design of channel transmissibility and may ultimately lead to improved permeability of compounds across bacterial outer membranes.

Year of Publication
2015
Journal
Chem Biol
Volume
22
Issue
4
Pages
535-47
Date Published
2015 Apr 23
ISSN
1879-1301
URL
DOI
10.1016/j.chembiol.2015.03.018
PubMed ID
25910245
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