A novel α-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized α-mangostin (α-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. α-MG-4, featuring an allyl group at C3 of the lead compound α-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although α-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio <i>in vitro</i> when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed <i>in vivo</i> using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that α-MG-4 was associated with changes in membrane permeability and inhibition of the <i>MepA</i> and <i>NorA</i> genes, which encode the efflux pumps of MRSA2. α-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.IMPORTANCEMethicillin-resistant <i>Staphylococcus aureus</i> (MRSA)'s resistance to multiple antibiotics poses significant health and safety concerns. A novel α-mangostin (α-MG) derivative, α-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of α-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function.