Targeting the permeability barrier and peptidoglycan recycling pathways to disarm Pseudomonas aeruginosa against the innate immune system

摘要: Antimicrobial resistance is a continuously increasing threat that severely compromises our antibiotic arsenal and causes thousands of deaths due to hospital-acquired infections by pathogens such as Pseudomonas aeruginosa, situation further aggravated the limited development new antibiotics. Thus, alternative strategies those targeting bacterial mechanisms, virulence or potentiating activity immune system resources are urgently needed. We have recently shown mutations simultaneously causing peptidoglycan recycling blockage β-lactamase AmpC overexpression impair P.aeruginosa. These findings suggested metabolism might be good target not only for fighting resistance, but also attenuation and/or potentiation innate weapons. Here we analyzed elements recognition proteins (PGRPs) lysozyme against P. aeruginosa. show while PGRPs very modest basal effect over their bactericidal dramatically increased in presence subinhibitory concentrations permeabilizing agent colistin. aeruginosa inhibitors seem play residual protective role even conditions. In contrast, demonstrate that, once permeability barrier overpassed, enhanced when inhibiting key components (such 3 AmpDs, AmpG NagZ), indicating decisive cell-wall direct peptidoglycan-binding supports, at least partially, these enzymes. Finally, blockade occurring with determines decrease PGRP2 lysozyme, linked quantitative changes cell-wall. results help delineate infections, β-lactam virulence, ultimately enhancing