Methylation of Daptomycin Leading to the Discovery of Kynomycin, a Cyclic Lipodepsipeptide Active against Resistant Pathogens

Increased usage of daptomycin to treat infections caused by Gram-positive
bacterial pathogens has resulted in emergence of resistant mutants.
In a search for more effective daptomycin analogues through medicinal
chemistry studies, we found that methylation at the nonproteinogenic
amino acid kynurenine in daptomycin could result in significant enhancement
of antibacterial activity. Termed “kynomycin,” this
new antibiotic exhibits higher antibacterial activity than daptomycin
and is able to eradicate methicillin-resistant Staphylococcus
aureus (MRSA) and vancomycin-resistant Enterococcus
(VRE) strains, including daptomycin-resistant strains. The
improved antimicrobial activity of kynomycin was demonstrated in in
vitro time-killing assay, in vivo wax worm model, and different mouse
infection models. The increased antibacterial activity, improved pharmacokinetics,
and lower cytotoxicity of kynomycin, compared to daptomycin, showed
the promise of the future design and development of next-generation
daptomycin-based antibiotics.