Fitness of Salmonella mutants resistant to antimicrobial peptides

J Antimicrob Chemother. 2015 Feb;70(2):432-40. doi: 10.1093/jac/dku423. Epub 2014 Oct 31.

Abstract

Objectives: To examine the effects of mutations in the waaY, phoP and pmrB genes, which confer resistance to antimicrobial peptides (AMPs), on fitness of Salmonella Typhimurium.

Methods: Survival during low pH, oxidative stress, stationary-phase incubation, exposure to serum and bile and growth in mice and laboratory media were determined by time-kills, disc inhibition assays, competition experiments and optical density measurements.

Results: Individual mutations in the waaY gene (involved in LPS core biosynthesis) and in the phoP and pmrB genes (part of two different two-component regulatory systems, phoPQ and pmrAB) conferred no or minor effects on bacterial survival during stressful in vitro conditions or in mice. In contrast, a waaY-phoP-pmrB triple mutant was compromised under most assay conditions.

Conclusions: Results from this study show that AMP resistance can be cost-free, as assessed by several assays that attempt to mimic the conditions a bacterium might encounter within a host. Our findings imply that future therapeutic use of AMPs could select for fit mutants with cross-resistance to human defence peptides and that potential resistance development in response to therapeutic use of AMPs needs to be carefully monitored.

Keywords: Salmonella Typhimurium, resistance; bile; growth rate; mice; oxidative stress; pH response; serum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antimicrobial Cationic Peptides / pharmacology*
  • Bile
  • Drug Resistance, Bacterial*
  • Gene Expression Regulation, Bacterial / drug effects
  • Genetic Fitness*
  • Hydrogen-Ion Concentration
  • Lipopolysaccharides / metabolism
  • Mice
  • Microbial Viability / drug effects
  • Microbial Viability / genetics
  • Mutation*
  • Oxidative Stress
  • Salmonella / drug effects*
  • Salmonella / genetics*
  • Salmonella / growth & development
  • Salmonella / metabolism
  • Salmonella typhimurium / drug effects
  • Salmonella typhimurium / genetics

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Lipopolysaccharides