Identifying and exploiting genes that potentiate the evolution of antibiotic resistance

Danna R. Gifford*, Victoria Furió, Andrei Papkou, Tom Vogwill, Antonio Oliver, R. Craig MacLean

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

There is an urgent need to develop novel approaches for predicting and preventing the evolution of antibiotic resistance. Here, we show that the ability to evolve de novo resistance to a clinically important β-lactam antibiotic, ceftazidime, varies drastically across the genus Pseudomonas. This variation arises because strains possessing the ampR global transcriptional regulator evolve resistance at a high rate. This does not arise because of mutations in ampR. Instead, this regulator potentiates evolution by allowing mutations in conserved peptidoglycan biosynthesis genes to induce high levels of β-lactamase expression. Crucially, blocking this evolutionary pathway by co-Administering ceftazidime with the β-lactamase inhibitor avibactam can be used to eliminate pathogenic P. aeruginosa populations before they can evolve resistance. In summary, our study shows that identifying potentiator genes that act as evolutionary catalysts can be used to both predict and prevent the evolution of antibiotic resistance.

Original languageEnglish
Pages (from-to)1033-1039
Number of pages7
JournalNature Ecology & Evolution
Volume2
Early online date23 Apr 2018
DOIs
Publication statusPublished - Apr 2018

Keywords

  • PSEUDOMONAS-AERUGINOSA AMPR
  • BETA-LACTAM RESISTANCE
  • SEQUENCING DATA
  • FLOW-CYTOMETRY
  • POPULATION
  • EXPRESSION
  • VIRULENCE
  • GENOME
  • MECHANISMS
  • ADAPTATION

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