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

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

3 Scopus Citations
View graph of relations

Author(s)

  • Hoi Yee Chow
  • Kathy Hiu Laam Po
  • Peng Gao
  • Pilar Blasco
  • Xiukun Wang
  • Congran Li
  • Lianwei Ye
  • Kang Jin
  • Kaichao Chen
  • Edward Wai Chi Chan
  • Xuefu You
  • Richard Yi Tsun Kao
  • Xuechen Li

Detail(s)

Original languageEnglish
Pages (from-to)3161-3171
Journal / PublicationJournal of Medicinal Chemistry
Volume63
Issue number6
Online published25 Feb 2020
Publication statusPublished - 26 Mar 2020

Abstract

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.

Citation Format(s)

Methylation of Daptomycin Leading to the Discovery of Kynomycin, a Cyclic Lipodepsipeptide Active against Resistant Pathogens. / Chow, Hoi Yee; Po, Kathy Hiu Laam; Gao, Peng; Blasco, Pilar; Wang, Xiukun; Li, Congran; Ye, Lianwei; Jin, Kang; Chen, Kaichao; Chan, Edward Wai Chi; You, Xuefu; Yi Tsun Kao, Richard; Chen, Sheng; Li, Xuechen.

In: Journal of Medicinal Chemistry, Vol. 63, No. 6, 26.03.2020, p. 3161-3171.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal