The role of mexZ in Pseudomonas aeruginosa infection transcends conventional antibiotic resistance perspectives

Pseudomonas aeruginosa is one of the microorganisms with high-risk regarding antimicrobial resistance, since it has an overwhelming capacity to acquire antibiotic resistance, mainly by mutations when establishing persistent lung infections. Mutations in mexZ, encoding the local negative regulator of genes encoding the MexXY efflux pump, are very frequently acquired at early stages of P. aeruginosa infections, while they are rarely selected for in vitro. Although traditionally related to resistance to the first-line drug tobramycin, caused by the overproduction of the aminoglycosides MexXY efflux pump, mutations in mexZ are actually associated with low levels of aminoglycosides resistance. This very mild but frequent phenotype suggests that these mutations may shape the infection process, beyond causing resistance. Here we investigated the colonization strategy of a mexZ mutant, compared to a wild-type strain, in a human airway infection model. We observed that the mexZ mutant accumulates inside the epithelial cell layer. This behaviour allows the bacterial population to colonise the epithelium while being more protected against diverse antibiotics. The altered colonization phenotype was caused by the overexpression of lecA, encoding a lectin involved in P. aeruginosa tissue invasiveness, which is regulated by quorum sensing. The cause was the competition for the shared porin, OprM, between the overproduced MexXY and the MexAB efflux pump, responsible for extruding quorum-sensing molecules. These findings offer an alternative explanation for antibiotic treatment failure based on host-microbe interaction dynamics altered by the evolution of antimicrobial resistance.