Mutations in mexT bypass the stringent response dependency of virulence in Pseudomonas aeruginosa

Pseudomonas aeruginosa produces a wealth of virulence factors whose production is controlled via an intricate regulatory systems network. Here, we uncover a major player in the evolution and regulation of virulence that enhances host colonization and antibiotic resistance. By characterizing a collection of mutants lacking the stringent response (SR), a system key for virulence, we show that the loss of the central regulator MexT bypasses absence of the SR, restoring full activation of virulence pathways. Notably, mexT mutations were associated with resistance to aminoglycosides and the last-resort antibiotic, colistin. Analysis of thousands of P. aeruginosa genomes revealed that mexT mutations are widespread in isolates linked to aggressive antibiotic treatment. Furthermore, in vivo experiments in a murine pulmonary model revealed that mexT mutants display a hypervirulent phenotype associated with bacteremia. Altogether, these findings uncover a key regulator that acts as a genetic switch in the regulation of virulence and antimicrobial resistance.