Roles of porin and beta-lactamase in beta-lactam resistance of Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa demonstrates high intrinsic resistance to most beta-lactam antibiotics. Two factors that are interrelated appear to be important in this intrinsic resistance: an inducible, chromosomally encoded type Id beta-lactamase and low outer-membrane permeability. beta-Lactamase-noninducible mutants are supersusceptible to many beta-lactam agents, whereas constitutively derepressed mutants are considerably more resistant even to so-called beta-lactamase-stable beta-lactams. For the latter mutants, by analysis of kinetics, it can be demonstrated that synergy between slow permeation across the outer membrane and slow hydrolysis of the beta-lactamase-stable beta-lactams can explain resistance. Wild-type P. aeruginosa allows outer membrane permeation of beta-lactam agents at rates 1%-8% of those measured for Escherichia coli. The majority of trans-outer-membrane channels formed by P. aeruginosa porin protein F are too small to allow passage of beta-lactam antibiotics. Nevertheless, this porin is apparently a conduit for beta-lactams, since protein F-deficient mutants have small changes in susceptibility to certain beta-lactam agents. This low outer-membrane permeability acting in synergy with beta-lactamase is probably responsible for intrinsic beta-lactam resistance in P. aeruginosa.