Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 6, Pages 3161-3171Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01957
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Funding
- Research Grants Council-Collaborative Research Fund of Hong Kong [C7038-15G, C5026-16G]
- Area of Excellence Scheme of the University Grants Committee of Hong Kong [AoE/P705/16]
- National Mega-project for Innovative Drugs [2018ZX09721001]
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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 dapto-mycin-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.
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