Rational Design of Natural Xanthones Against Gram‐negative Bacteria

Abstract Most antibiotics are ineffective against Gram‐negative bacteria owing to the existence of the outer membrane (OM) barrier. The rational design of compounds to expand their antibacterial spectra of antibiotics solely targeting Gram‐positive pathogens remains challenging. Here, the design of skeletons from natural products to penetrate the OM are deciphered. Structure‐activity relationship analysis shows the optimization of the model of natural xanthones α‐mangostin endows the broad‐spectrum antibacterial activity. Mechanistic studies demonstrate the lead compound A20 penetrates the OM in a self‐promoted pathway through electronic and hydrophobic interactions with lipopolysaccharides and phospholipids in OM. A20 displays rapid bactericidal activity by targeting the cofactor heme in the respiratory complex. The therapeutic efficacy of A20 is demonstrated in two animal models infected with multidrug‐resistant Gram‐negative bacterial pathogens. The findings elucidate the structural property and self‐promoted transportation of a class of antibacterial compounds, to facilitate the design and discovery of antibacterial agents against increasingly prevalent Gram‐negative pathogens associated with infections.