Isabella V.M.,Synlogic |
Campbell A.J.,The Broad Institute of MIT and Harvard |
Manchester J.,Astra Zeneca Infection Innovative Medicines |
Sylvester M.,Astra Zeneca Infection Innovative Medicines |
And 4 more authors.
Chemistry and Biology | Year: 2015
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. © 2015 Elsevier Ltd. All rights reserved.