Synthesis and Biological Evaluation of C6-O-Glycosylated α-Mangostin Derivatives Against Methicillin-Resistant Staphylococcus aureus With Enhanced Bacterial Membrane Selectivity.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major global health threat, driving demand for antibacterial agents with robust efficacy and low propensity for resistance. The natural xanthone α-mangostin (α-MG) shows potent anti-MRSA activity via membrane disruption, but its high hydrophobicity and hemolytic liability limit therapeutic potential. Here, we designed and synthesized a focused series of C6-O-glycosylated α-MG derivatives (Y-1-Y-15) bearing structurally diverse mono- and disaccharides to tune amphiphilicity and improve bacterial-versus-host selectivity. Among them, Y-3 (L-gulose conjugate) retained strong activity against both methicillin-susceptible S. aureus and MRSA (MIC = 2 μg/mL), while markedly reducing red blood cell lysis (HC50 = 48.20 μg/mL) and improving the selectivity index (SI = 24.10). Mechanistic assays showed that Y-3 rapidly permeabilized and depolarized bacterial membranes. In phospholipid antagonism experiments, anionic bacterial lipids (cardiolipin and phosphatidylglycerol) reduced Y-3 activity more strongly than phosphatidylcholine, supporting preferential interaction with bacterial-type membranes. In a murine MRSA wound infection model, topical Y-3 reduced bacterial burden and accelerated wound healing compared with the vehicle and α-MG. Together, this study identifies C6 glycosylation as a practical strategy to decouple the antibacterial efficacy of α-MG from host membrane toxicity and support Y-3 as a lead for topical anti-MRSA development.