Integrated evolutionary analysis reveals the resistance risk to antimicrobial peptides in Staphylococcus aureus

The safety risks of antimicrobial peptide (AMP) resistance have never been properly understood. Herein, we comprehensively investigated the evolution of resistance to AMPs in Staphylococcus aureus using piscidin1 (PIS-1) and piscidin3 (PIS-3) as archetypes, in which they were both combined with cell membranes via a common structural motif but vary in permeabilizing actions. The results demonstrated that the bacterial strain acquired limited resistance to PIS-3 compared to PIS-1. However, the PIS-3-induced strain developed parlous co-resistance toward PIS-1, ampicillin, ofloxacin, rifampicin, tetracycline, vancomycin, and polymyxin B. Based on the results of the chemiluminescence method, transcriptome sequencing and proteomic analysis, the generation of bacterial co-resistance was affiliated with decreased cell membrane permeability, mainly involving the regulation of the two-component system, ATP-binding cassette transporters and phosphotransferase system. These findings highlight concerns that AMPs could trigger a new crisis of drug resistance in food packaging, feed additives, and the agricultural environment.