Mutations in pmrB Confer Cross-Resistance between the LptD Inhibitor POL7080 and Colistin in Pseudomonas aeruginosa

Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00511-19. doi: 10.1128/AAC.00511-19. Print 2019 Sep.

Abstract

Pseudomonas aeruginosa is a major bacterial pathogen associated with a rising prevalence of antibiotic resistance. We evaluated the resistance mechanisms of P. aeruginosa against POL7080, a species-specific, first-in-class antibiotic in clinical trials that targets the lipopolysaccharide transport protein LptD. We isolated a series of POL7080-resistant strains with mutations in the two-component sensor gene pmrB Transcriptomic and confocal microscopy studies support a resistance mechanism shared with colistin, involving lipopolysaccharide modifications that mitigate antibiotic cell surface binding.

Keywords: POL7001; POL7080; Pseudomonas; antibiotic resistance; colistin; multidrug resistance; murepavadin; pmrB; polymyxins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Proteins / genetics
  • Colistin / pharmacology*
  • Drug Resistance, Bacterial / drug effects
  • Drug Resistance, Bacterial / genetics*
  • Gene Expression Regulation, Bacterial / drug effects
  • Microbial Sensitivity Tests
  • Mutation
  • Peptides, Cyclic / pharmacology*
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / genetics
  • Transcription Factors / genetics

Substances

  • Anti-Bacterial Agents
  • Bacterial Outer Membrane Proteins
  • Bacterial Proteins
  • Peptides, Cyclic
  • PmrB protein, bacteria
  • Transcription Factors
  • murepavadin
  • Colistin