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 (HC 50 = 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.