Mechanistic insights into the multitarget synergistic efficacy of farrerol and β-lactam antibiotics in combating methicillin-resistant <i>Staphylococcus aureus</i>

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), a principal causative agent of infections worldwide, urgently requires innovative interventions to counter its increasing risk. The present study revealed the profound impact of farrerol (FA), a robust bioactive agent, on the virulence and resistance mechanisms of MRSA. Our in-depth investigation revealed that FA significantly mitigated the β-lactam resistance of MRSA USA300, an achievement attributed to its precise interference with the BlaZ and Pbp2a protein. Additionally, FA indirectly diminishes the oligomerization of PBP2a by disrupting pigment synthesis, further contributing to its efficacy. In addition, FA extends its functional footprint beyond resistance modulation, exhibiting substantial antivirulence efficacy through selective inhibition of the accessory gene regulator (Agr) system, thereby significantly curbing MRSA pathogenicity in A549 cell and murine models. This study comprehensively explored the multiple impacts of FA on MRSA, shedding light on its versatile role as a BlaZ suppressor, pigment synthesis regulator, and AgrA activity modulator. These intricate findings firmly position FA as a compelling therapeutic candidate for addressing MRSA infections in the clinic.