Distribution of Lantibiotic Susceptibility and Its Association With Two‐Component Regulatory Systems in <i>Staphylococcus aureus</i> Clinical Isolates

Bacteriocins, antimicrobial peptides produced by bacteria, are expected to be novel antimicrobial agents. Previous studies demonstrated that several two-component regulatory systems (TCSs) linked to the expression of lantibiotic transporters are involved in resistance to lantibiotics in Staphylococcus aureus. In this study, we examined the susceptibility to four Class Ia bacteriocins (lantibiotics) among clinical isolates of S. aureus and sought to reveal the mechanisms underlying differences in susceptibility among strains. A direct assay was performed using nisin A, Pep5, nukacin ISK-1, and epidermin-producing strains to examine the susceptibility of 149 S. aureus isolates isolated from nasal cavity or bloodstream infections. Among them, some strains showed significantly higher susceptibility to epidermin, nukacin ISK-1, and nisin A. These strains did not show the induction of transporter-encoded vraD expression in the presence of nisin A, suggesting impaired TCS BraRS function. Some strains harbored frameshifts or nonsense mutations in braR, braA, and braB or the absence of transporter-encoded vraDEH genes. In addition, strains with frameshifts in TCS GraR and transporter VraG genes showed increased susceptibility to nisin A, Pep5, and nukacin ISK-1. When comparing the susceptibility among MLST-defined clonal complexes (CCs), CC45 showed higher susceptibility to nisin A, Pep5, and nukacin ISK-1, while CC5 exhibited low susceptibility to them. CC45 also showed higher susceptibility within the BraRS-disrupted strains. The net negative charge of the cell surface did not vary significantly among CCs, suggesting the involvement of factors other than BraRS and GraRS. These findings provide important insights for evaluating bacteriocins as novel antimicrobial agents against S. aureus.