Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA)

Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA)
Li Ren, Lin Wang, Shouping Liu, Lei Zhou, Roger W. Beuerman, Jun-Jie Koh, Wan Ling Wendy Sin, Donald T. H. Tan, Rajamani Lakshminarayanan, Shuimu Lin, Derong Cao, Fanghui Lim, Thet Tun Aung
A new series of semisynthetic flavone-based small molecules mimicking antimicrobial peptides has been designed from natural icaritin to combat drug-resistant Gram-positive bacterial infections. Compound 6 containing two arginine residues exhibited excellent antibacterial activity against Gram-positive bacteria, including MRSA, and very low toxicity to mammalian cells, resulting in a high selectivity of more than 511, comparable to that of several membrane-active antibiotics in clinical trials. Our data show for the first time that icaritin derivatives effectively kill bacteria. Meanwhile, this is the first study deploying a biomimicking strategy to design potent flavone-based membrane targeting antimicrobials. 6 showed rapid bactericidal activity by disrupting the bacterial membrane and can circumvent the development of bacterial resistance. Importantly, 6 was highly efficacious in a mouse model of corneal infection caused by MRSA and Staphylococcus aureus.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00380

DOI: 10.1021/acs.jmedchem.7b00380

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