Discovery of Cationic Lugdunin Derivatives with Membrane-Disrupting Activity against Resistant Bacteria via Radical Reactions and Amino Acid Mutations

Lugdunin
was the first reported new class of thiazolidine
cyclopeptide
antibiotic from human microbiomes. However, its structure could not
accommodate polar amino acids or modules, limiting its potential for
chemical modification and clinical application. Herein, we developed
a combinatorial modification strategy based on in situ modification
of tryptophan through a radical reaction and amino acid site-specific
mutation, transforming lugdunin into a cationic cyclic peptide antibiotic.
Among the derivatives of lugdunin, WK6 was identified as a highly
potent membrane-active antibiotic with rapid bactericidal activity
and low resistance development potential. Remarkably, it showed therapeutic
efficacy in MRSA-infected murine models of keratitis, pneumonia, and
peritonitis. Additionally, when grafted onto contact lens Surfaces,
WK6 exhibited potent antifouling capabilities, highlighting its potential
in implant antifouling applications. Therefore, this study developed
an effective strategy to optimize lugdunin and unveiled a novel cationic
lugdunin derivative WK6, which could be recognized as a promising
lead compound to combat multidrug-resistant bacteria.