Xanthocillin X combats Burkholderia pseudomallei by targeting UDP-N-acetylglucosamine acyltransferase

Drug-resistance in Burkholderia pseudomallei (B. pseudomallei) and the limited ability of antibiotics to eradicate biofilms underscore the urgent need for alternative therapeutic options. New drugs which suppress the biofilm formation without emergence of antimicrobial resistance have clearly attracted global attention. We report a deep-sea-derived natural product xanthocillin X (Xan) for the therapeutic of B. pseudomallei 1 induced infections. Xan possesses superior antibacterial ability over commercial ceftazidime even at an ultralow concentration of 62.5 ng/mL, and can inhibit the formation of biofilm with high efficiency without drug resistance. Specially, Xan demonstrates stable binding ability with LpxA which is responsible for lipopolysaccharide synthesis, and thus disrupting the formation of biofilm. In two murine models, Xan exhibits therapeutic potency for combating B. pseudomallei 1 induced infections. Taken together, Xan that specifically interacts with LpxA impairs the formation of biofilm without drug resistance, endowing the compound with dominant antibacterial activity and accelerating tissue repair after infection.