Fitness of Salmonella mutants resistant to antimicrobial peptides

Area of Science:

• Microbiology
• Bacterial genetics
• Antimicrobial resistance

Background:

• Antimicrobial peptides (AMPs) are crucial components of the innate immune system.
• Mutations in waaY, phoP, and pmrB genes confer resistance to AMPs in Salmonella Typhimurium.
• Understanding the fitness costs associated with AMP resistance is vital for predicting therapeutic outcomes.

Purpose of the Study:

• To investigate the impact of specific gene mutations (waaY, phoP, pmrB) on the fitness of Salmonella Typhimurium.
• To assess the survival and growth of mutant strains under various stress conditions.
• To evaluate the implications of AMP resistance for bacterial adaptation and host defense.

Main Methods:

• Assessing bacterial survival through time-kill assays and disc inhibition tests.
• Evaluating growth dynamics using optical density measurements and competition experiments.
• Testing bacterial fitness under conditions simulating host environments, including low pH, oxidative stress, serum, and bile exposure, as well as in vivo mouse models.

Main Results:

• Single mutations in waaY, phoP, or pmrB genes had minimal impact on Salmonella Typhimurium fitness under tested conditions.
• A waaY-phoP-pmrB triple mutant exhibited significantly compromised survival and growth across multiple in vitro and in vivo assays.
• AMP resistance can be achieved with little to no fitness cost in Salmonella Typhimurium.

Conclusions:

• AMP resistance can be phenotypically neutral, posing a challenge for host defense.
• Therapeutic use of AMPs may inadvertently select for highly fit, resistant bacterial mutants.
• Close monitoring for the emergence of cross-resistance to host defense peptides is recommended during AMP treatment.