Mutations in mexT bypass the stringent response dependency of virulence in Pseudomonas aeruginosa
Wendy Figueroa,
Adrian Cazares,
Eleri A. Ashworth,
Aaron Weimann,
Aras Kadioglu,
R. Andres Floto,
Martin Welch
Affiliations
Wendy Figueroa
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK; Corresponding author
Adrian Cazares
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
Eleri A. Ashworth
Department of Clinical Infection, Microbiology & Immunology, University of Liverpool, Liverpool L69 7BE, UK
Aaron Weimann
Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK; Molecular Immunity Unit, University of Cambridge, Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK
Aras Kadioglu
Department of Clinical Infection, Microbiology & Immunology, University of Liverpool, Liverpool L69 7BE, UK
R. Andres Floto
Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK; Molecular Immunity Unit, University of Cambridge, Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK
Martin Welch
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Corresponding author
Summary: 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.
