Rosmarinic Acid Restores the Ceftiofur Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus by Inhibiting Sortase A

Methicillin-resistant Staphylococcus aureus (MRSA), one of the most important zoonotic bacterial pathogens, necessitates innovative antibacterial strategies. Rosmarinic acid (RA) possesses various biological functions, including antibacterial and anti-inflammatory effects. This study aimed to explore the synergistic effects and mechanism of RA in conjunction with ceftiofur (CF) against MRSA. Results showed that the combination of RA and CF demonstrated synergistic anti-MRSA activity, conferring protective effects in an MRSA bacteremia mouse model. Mechanistic investigations further established that RA interacts with sortase A (SrtA) through hydrogen bonds, electrostatic, and van der Waals forces at critical sites, leading to the reversible inhibition of SrtA activity. Consequently, this inhibition impeded the ability of MRSA to invade cells and form biofilms. Conclusively, RA directly inhibits SrtA activity, thus enhancing the synergistic anti-MRSA effect of CF. These findings provide a theoretical foundation for the use of RA in combination with CF as a therapeutic strategy for MRSA infections.