Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides

Area of Science:

• Microbiology
• Immunology
• Drug Discovery

Background:

• Antimicrobial peptides (AMPs) are being developed to combat multidrug-resistant (MDR) bacterial pathogens.
• The long-term effects of bacterial exposure to AMPs are not fully understood, despite their similarity to human innate immune components.

Purpose of the Study:

• To investigate the development of resistance in Staphylococcus aureus (MRSA) upon serial passage in the presence of host-derived AMPs.
• To understand the molecular mechanisms, fitness costs, and cross-resistance profiles of AMP-resistant MRSA mutants.

Main Methods:

• Serial passage of a clinical MRSA strain (USA300) with increasing concentrations of AMPs (LL-37, PR-39, wheat germ histones).
• Whole Genome Sequencing (WGS) and proteomic analysis (Mass Spectrometry) to identify resistance mechanisms.
• Characterization of AMP-resistant mutants for in vitro fitness, susceptibility to AMPs and antibiotics, and in vivo virulence in a mouse sepsis model.

Main Results:

• Stable AMP resistance was selected in MRSA after serial passage in a host-mimicking environment.
• AMP-resistant mutants exhibited minimal fitness costs and retained virulence in a mouse model.
• AMP resistance correlated with reduced susceptibility to conventional antibiotics and human defense peptides.

Conclusions:

• Therapeutic use of AMPs may inadvertently select for virulent MRSA mutants with cross-resistance to both antibiotics and innate immunity.
• Careful monitoring and evaluation of AMPs' therapeutic use and potential cross-resistance implications are crucial.