A MexR Mutation Which Confers Aztreonam Resistance to Pseudomonas aeruginosa

Therapy for Pseudomonas aeruginosa infections is hard due to its high natural and acquirable antibiotic resistance. After colonization in the hosts, P. aeruginosa commonly accumulates genomic mutations which confer them antibiotic resistance and better adaptations to the host environment. Deciphering the mechanisms of antibiotic resistance development in the clinical setting may provide critical insights into the design of effective combinatory antibiotic therapies to treat P. aeruginosa infections. In this work, we demonstrate a resistance mechanism to aztreonam of a clinical isolate (ARP36) in comparison with a sensitive one (CSP18). RNAseq and genomic DNA resequencing were carried out to compare the global transcriptional profiles and in the clinical setting genomic profiles between these two isolates. The results demonstrated that hyperexpression of an efflux pump MexAB-OprM caused by a R70Q substitution in MexR, contributed to the increased resistance to aztreonam in the isolate ARP36. Simulation of mexR of ARP36 by gene editing in CSP18 conferred CSP18 an ARP36-like susceptibility to the aztreonam. The R70Q substitution prevented MexR from binding to the intergenic region between mexR and mexAB-oprM operon, with no impact on its dimerization. The presented experimental results explain for the first time why the clinically relevant R70Q substitution in the MexR derepresses the expression of mexAB-oprM in P. aeruginosa.