People with cystic fibrosis (CF) suffer from life-threatening antibiotic-resistant Pseudomonas aeruginosa respiratory infections, with consequent chronic inflammation, which generates oxidative stress. P. aeruginosa expresses several multidrug efflux systems, including the MexXY-OprM pump, which drives antimicrobial resistance in CF lungs. Expression of MexXY-OprM is unexpected, because ribosome disruption, but not antibiotics such as aminoglycosides, induces its expression, yet CF isolates exhibit high degrees of resistance to aminoglycosides. It turns out that mexXY up-regulation depends on the gene PA5471, which is induced by oxidative stress. Fraud and Poole now demonstrate that exposure to inflammation-induced oxidative stress for several days produced a fourfold elevation in aminoglycoside resistance in P. aeruginosa, which was indeed mediated by PA5471. Aminoglycoside resistance did not always follow increased mexXY expression alone, which suggests that additional genes required for translation or protein synthesis may be involved. Thus, chronic inflammation, rather than antibiotics, drives the expression of MexXY-OprM, which leads to drug resistance in CF lungs.

source:Antimicrobial Agents Chemotherapy.