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

doi:10.1016/j.celrep.2024.115079

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

Cell Rep. 2024 Dec 20;44(1):115079. doi: 10.1016/j.celrep.2024.115079. Online ahead of print.

Authors

Wendy Figueroa¹, Adrian Cazares², Eleri A Ashworth³, Aaron Weimann⁴, Aras Kadioglu³, R Andres Floto⁵, Martin Welch⁶

Affiliations

¹ 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. Electronic address: [email protected].
² Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
³ Department of Clinical Infection, Microbiology & Immunology, University of Liverpool, Liverpool L69 7BE, UK.
⁴ 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.
⁵ 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.
⁶ Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK. Electronic address: [email protected].

PMID: 39708318
DOI: 10.1016/j.celrep.2024.115079

Abstract

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.

Keywords: CP: Microbiology; MexT; Pseudomonas aeruginosa; antimicrobial resistance; genetic switch; hypervirulence; pathogen evolution; quorum sensing; regulatory network; stringent response; transcriptome.