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

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.