Pan-Ras-In-1 triggers cell wall lysis to eradicate Staphylococcus aureus

Abstract

Summary Given the global crisis of antimicrobial resistance, the dual anticancer and antibacterial properties of certain agents have attracted increasing attention as a potential alternative to conventional antimicrobial approaches. In this study, we characterized the bactericidal activity of an anticancer molecule (Pan-Ras-In-1) against Staphylococcus aureus, a pathogen associated with refractory infection. In vitro assays revealed that Pan-Ras-In-1 has a more pronounced bactericidal effect on S. aureus cells than the traditional antibiotics vancomycin and levofloxacin. Furthermore, Pan-Ras-In-1 displayed potential therapeutic efficacy in vivo, as assessed using the murine systemic infection and skin abscess models, suggesting its potential for subsequent clinical applications. Exposure of S. aureus to Pan-Ras-In-1 activates CidA-associated peptidoglycan hydrolase systems, which partially mediate bacterial programmed cell death. Peptide-centric local stability analyses revealed that Pan-Ras-In-1 binds to TarA protein, suppressing wall teichoic acid polymer production. The combined action of two mechanisms enables Pan-Ras-In-1 to compromise bacterial cell wall integrity.