Antimicrobial resistance of Staphylococcus aureus by quantitative proteomics with TMT-labelling

The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in multi-drug resistant bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system, and the ramifications of prolonged bacterial exposure to AMPs are not fully understood. Here we show that in vitro serial passage of a clinical USA300 methicillin-resistant Staphylococcus aureus strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP-resistance. AMP-resistant S. aureus mutants often displayed little to no fitness cost and caused invasive disease in mice. Further, this phenotype coincided with diminished susceptibility to both clinically prescribed antibiotics and human defense peptides. These findings suggest that therapeutic use of AMPs could select for virulent mutants with cross-resistance to human innate immunity as well as antibiotic therapy. Thus, therapeutic use of AMPs and the implications of cross-resistance need to be carefully monitored and evaluated.