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Generation of In-Frame Gene Deletion Mutants in Pseudomonas aeruginosa and Testing for Virulence Attenuation in a Simple Mouse Model of Infection
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Mutations in mexT bypass the stringent response dependency of virulence in Pseudomonas aeruginosa

Wendy Figueroa1, Adrian Cazares2, Eleri A Ashworth3

  • 1Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK.

Cell Reports
|December 21, 2024
PubMed

Insights

The stringent response regulator MexT controls Pseudomonas aeruginosa virulence and antibiotic resistance. Loss of MexT bypasses stringent response defects, enhancing virulence and conferring resistance to critical antibiotics like colistin.

Area of Science:

  • Microbiology
  • Bacterial Pathogenesis
  • Genetics

Background:

  • Pseudomonas aeruginosa possesses complex regulatory networks controlling virulence factors.
  • The stringent response (SR) is crucial for P. aeruginosa virulence.
  • Understanding these regulatory systems is key to combating antibiotic resistance.

Purpose of the Study:

  • To identify key regulators involved in P. aeruginosa virulence and antibiotic resistance.
  • To investigate the role of the MexT regulator in relation to the stringent response.
  • To explore the evolutionary and regulatory significance of mexT mutations.

Main Methods:

  • Characterization of P. aeruginosa mutants lacking the stringent response.
  • Analysis of mexT mutations in P. aeruginosa isolates.
  • In vivo experiments using a murine pulmonary infection model.

Main Results:

  • Loss of the central regulator MexT restored virulence in stringent response-deficient mutants.
  • mexT mutations were strongly associated with resistance to aminoglycosides and colistin.
  • mexT mutants exhibited hypervirulence and bacteremia in a murine model.
  • Genomic analysis revealed widespread mexT mutations in isolates from patients undergoing aggressive antibiotic treatment.

Conclusions:

  • MexT acts as a critical genetic switch regulating both virulence and antimicrobial resistance in P. aeruginosa.
  • mexT mutations represent an adaptive evolutionary mechanism enhancing bacterial survival and pathogenicity.
  • Targeting MexT could offer novel strategies against multidrug-resistant P. aeruginosa infections.
Keywords:
CP: MicrobiologyMexTPseudomonas aeruginosaantimicrobial resistancegenetic switchhypervirulencepathogen evolutionquorum sensingregulatory networkstringent responsetranscriptome

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