MSI-1 combats drug-resistant S. aureus by affecting bacterial viability and inhibiting carotenoid pigment production.

A schematic diagram depicting possible mechanism underlying the antimicrobial effects of MSI-1 against drug-resistant S. aureus , including MRSA, VISA and VRSA. MSI-1 could interact with CrtN to suppress its enzyme activity to reduce STX production at sub-MIC levels, thus attenuating local injury and systemic infection in vivo. (Figure partially created using BioRender, https://biorender.com/). [Display omitted] • MSI-1 interacted with CrtN to suppress its enzyme activity to reduce STX production. • The assistance of sub-MICs MSI-1 could sensitize pigmented S. aureus to immune clearance. • MSI-1 had potent activity against drug-resistant S. aureus, including MRSA and VRSA. • MSI-1 can be developed as a new antibacterial agent to resist refractory S. aureus infection. Development of novel therapeutic strategies and antibacterial agents against antibiotic-resistant Staphylococcus aureus (S. aureus) is urgent. In this study, antibacterial activities and possible mechanisms of peptide MSI-1 against multiple drug-resistant S. aureus were investigated. Results demonstrated that MSI-1 had potent bacteriostatic activity and bactericidal efficiency against S. aureus , including methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 4 to 16 μg/mL and bactericidal times from 2–12 h. MSI-1 exhibited a low incidence of developing resistance and additive effects with vancomycin to overcome MRSA and VRSA. Moreover, MSI-1, even at sub-MIC concentrations, inhibited staphyloxanthin (STX) production of S. aureus. This inhibitory effect was unique and effectively sensitized S. aureus to host immune defense. In terms of its modes of action, MSI-1 disrupted the cell membrane of S. aureus by binding to negatively-charged lipoteichoic acid to exert a direct bactericidal effect. Interestingly, MSI-1 interacted with 4,4′-diapophytoene desaturase (CrtN) of S. aureus via ionic bonds, hydrogen bonds, and Pi-Pi or Pi-alkyl interactions, and alanine substitution of the key amino acids contributed to these interactions weakened this STX production inhibition. Thus, in a MRSA-induced skin infection in mice and MRSA/VRSA-induced systemic infection in Galleria mellonella, MSI-1 alleviated staphylococcal scalded skin syndrome to promote mouse skin wound repair and mitigated staphylococcus infection-induced immune melanization to enhance G. mellonella survival. Collectively, MSI-1 has potent antibacterial activity against drug-resistant S. aureus by affecting bacterial viability and exerting its anti-virulence effects. It can be developed as a new antibacterial agent to resist refractory S. aureus infection. [ABSTRACT FROM AUTHOR]