The Two-component Regulatory Systems GraRS and SrrAB Mediate Susceptibility to Pep5 Produced by Clinical Isolate of

is a common bacterium on the skin and in the nose that sometimes causes severe illness. Bacteriocins, antimicrobial peptides, or proteins produced by bacteria are candidates for the treatment of infection. In this study, we found that a clinical strain, KSE112, produced the lantibiotic Pep5, which showed anti- activity. The complete nucleotide sequence of the Pep5-encoding plasmid was determined. Several two-component regulatory systems (TCSs) are known to be involved in bacteriocin susceptibility. Therefore, susceptibility tests were performed using TCS-inactivated mutants to determine which TCS is responsible for Pep5 susceptibility; the Δ mutant exhibited increased susceptibility to Pep5, while the Δ mutant exhibited decreased susceptibility. GraRS is known to regulate and in concert with , and Pep5 susceptibility was significantly increased in the Δ Δ and Δ mutants. Regarding the Δ mutant, cross-resistance to aminoglycosides was observed. As aminoglycoside activity is known to be affected by aerobic respiration, we focused on and which are quinol oxidase genes that are necessary for aerobic respiration and have downregulated the expression in the Δ mutant. We constructed Δ and Δ mutants and found that inactivation decreased susceptibility to Pep5 and aminoglycosides. These results indicate that reduced aerobic respiration due to the reduced expression in the Δ mutant decreased Pep5 activity.IMPORTANCEThe emergence of drug-resistant bacteria, including MRSA, is a severe health problem worldwide. Thus, the development of novel antimicrobial agents, including bacteriocins, is needed. In this report, we found a Pep5-producing strain with anti-. activity. We determined the complete sequence of the Pep5-encoding plasmid for the first time. However, in GraRS and its effectors conferred decreased susceptibility to Pep5. We also revealed that another TCS, SrrAB, affects susceptibility Pep5 and other lantibiotics by controlling aerobic respiration. In our study, we investigated the efficacy of Pep5 against and other Gram-positive bacteria and revealed that respiratory constancy regulated by TCS is required for the antimicrobial activity of nisin, nukacin, and Pep5. These findings provide important information for the clinical application of bacteriocins and suggest that they have different properties among similar pore-forming lantibiotics.