Triphenyl-sesquineolignan analogues derived from Illicium simonsii Maxim exhibit potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) by disrupting bacterial membranes.

Abstract Infections caused by clinical methicillin-resistant Staphylococcus aureus (MRSA) are a serious public problem. Triphenyl-sesquineolignans from Illicium genus possess antibacterial activity, but few researches have reported their antibacterial spectrums, structure-activity relationships (SARs) and antibacterial mechanism. In this study, three triphenyl-sesquineolignans, dunnianol (1), macranthol (2) and isodunnianol (3) were isolated from the stems and leaves of I. simonsii Maxim, and seven dunnianol derivatives were prepared through esterification, etherification and halogenation reactions. Among all triphenyl-sesquineolignan analogues, compound 6 showed the best antibacterial activity against four Gram-positive bacteria (MICs = 1–2 µg/mL) and ten clinical MRSA strains (MICs = 2–8 µg/mL), and also exhibited characteristics of killing MRSA more rapidly than tigecycline. Meanwhile, compound 6 did not only show a low probability of drug resistance development, but also exhibited relatively low hemolysis, and good stability in 50% plasma. Further mechanism studies revealed that 6 could kill bacterial strains by disrupting bacterial membranes. These results suggested that 6 may be developed into a new antibacterial candidate for combating MRSA infections.