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

J Med Chem. 2020 Mar 26;63(6):3161-3171. doi: 10.1021/acs.jmedchem.9b01957. Epub 2020 Mar 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / therapeutic use*
  • Anti-Bacterial Agents / toxicity
  • Cell Membrane Permeability / drug effects
  • Daptomycin / chemistry
  • Daptomycin / therapeutic use
  • Depsipeptides / chemical synthesis
  • Depsipeptides / pharmacokinetics
  • Depsipeptides / therapeutic use*
  • Depsipeptides / toxicity
  • Drug Resistance, Bacterial / drug effects
  • Enterococcus / drug effects
  • Female
  • HEK293 Cells
  • Humans
  • Lepidoptera / drug effects
  • Lepidoptera / microbiology
  • Lipopeptides / chemical synthesis
  • Lipopeptides / pharmacokinetics
  • Lipopeptides / therapeutic use*
  • Lipopeptides / toxicity
  • Male
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methylation
  • Mice, Inbred BALB C
  • Mice, Inbred ICR
  • Microbial Sensitivity Tests
  • Staphylococcal Infections / drug therapy*


  • Anti-Bacterial Agents
  • Depsipeptides
  • Lipopeptides
  • Daptomycin