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

TitleMethylation of Daptomycin Leading to the Discovery of Kynomycin, a Cyclic Lipodepsipeptide Active against Resistant Pathogens
Authors
Keywordsabdominal infection
animal cell
animal experiment
animal model
animal tissue
Issue Date2020
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/jmc
Citation
Journal of Medicinal Chemistry, 2020, v. 63 n. 6, p. 3161-3171 How to Cite?
AbstractIncreased 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.
Persistent Identifierhttp://hdl.handle.net/10722/284014
ISSN
2019 Impact Factor: 6.205
2015 SCImago Journal Rankings: 2.529
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChow, HY-
dc.contributor.authorPo, KHL-
dc.contributor.authorGao, P-
dc.contributor.authorBlasco, P-
dc.contributor.authorWang, X-
dc.contributor.authorLi, C-
dc.contributor.authorYe, L-
dc.contributor.authorJin, K-
dc.contributor.authorChen, K-
dc.contributor.authorChan, EWC-
dc.contributor.authorYou, X-
dc.contributor.authorKao, RYT-
dc.contributor.authorChen, S-
dc.contributor.authorLi, X-
dc.date.accessioned2020-07-20T05:55:20Z-
dc.date.available2020-07-20T05:55:20Z-
dc.date.issued2020-
dc.identifier.citationJournal of Medicinal Chemistry, 2020, v. 63 n. 6, p. 3161-3171-
dc.identifier.issn0022-2623-
dc.identifier.urihttp://hdl.handle.net/10722/284014-
dc.description.abstractIncreased 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.-
dc.languageeng-
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/jmc-
dc.relation.ispartofJournal of Medicinal Chemistry-
dc.subjectabdominal infection-
dc.subjectanimal cell-
dc.subjectanimal experiment-
dc.subjectanimal model-
dc.subjectanimal tissue-
dc.titleMethylation of Daptomycin Leading to the Discovery of Kynomycin, a Cyclic Lipodepsipeptide Active against Resistant Pathogens-
dc.typeArticle-
dc.identifier.emailChow, HY: hchowhy@connect.hku.hk-
dc.identifier.emailGao, P: gaopeng@hku.hk-
dc.identifier.emailBlasco, P: pbmoral@hku.hk-
dc.identifier.emailKao, RYT: rytkao@hkucc.hku.hk-
dc.identifier.emailLi, X: xuechenl@hku.hk-
dc.identifier.authorityKao, RYT=rp00481-
dc.identifier.authorityLi, X=rp00742-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/acs.jmedchem.9b01957-
dc.identifier.pmid32097000-
dc.identifier.scopuseid_2-s2.0-85082542503-
dc.identifier.hkuros310985-
dc.identifier.volume63-
dc.identifier.issue6-
dc.identifier.spage3161-
dc.identifier.epage3171-
dc.identifier.isiWOS:000526404600027-
dc.publisher.placeUnited States-
dc.identifier.issnl0022-2623-

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