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Article: An atomic perspective on improving daptomycin’s activity

TitleAn atomic perspective on improving daptomycin’s activity
Authors
KeywordsDaptomycin
Calcium dependent antibiotics
Oligomerization
Nuclear magnetic resonance (NMR)
Molecular dynamics (MD)
Issue Date2021
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/issn/03044165
Citation
Biochimica et Biophysica Acta (BBA) - General Subjects, 2021, v. 1865 n. 8, p. article no. 129918 How to Cite?
AbstractBackground: Recently, through comprehensive medicinal chemistry efforts, we have found a new daptomycin analogue, termed kynomycin, showing enhanced activity against both methicillin-resistant S. aureus and vancomycin-resistant Enterococcus in vitro and in vivo, with improved pharmacokinetics and lower cytotoxicity than daptomycin. Methods: In this study we compared the physicochemical properties of kynomycin with those of daptomycin from an atomic perspective by using Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations. Results and conclusion: We observed that kynurenine methylation changes daptomycin’s key physicochemical properties; its calcium dependent oligomerization efficiency is improved and the modified kynurenine strengths contacts with the lipid tail and tryptophan residues. In addition, it is observed that, compared to daptomycin, kynomycin tetramer is more stable and binds stronger to calcium. The combined experiments provide key clues for the improved antibacterial activity of kynomycin. General significance: We expect that this approach will help study the calcium binding and oligomerization features of new calcium dependent peptide antibiotics.
Persistent Identifierhttp://hdl.handle.net/10722/300841
ISSN
2020 Impact Factor: 3.77
2015 SCImago Journal Rankings: 2.128

 

DC FieldValueLanguage
dc.contributor.authorBlasco Morales, P-
dc.contributor.authorZhang, C-
dc.contributor.authorChow, HY-
dc.contributor.authorChen, G-
dc.contributor.authorWu, Y-
dc.contributor.authorLi, X-
dc.date.accessioned2021-07-06T03:10:57Z-
dc.date.available2021-07-06T03:10:57Z-
dc.date.issued2021-
dc.identifier.citationBiochimica et Biophysica Acta (BBA) - General Subjects, 2021, v. 1865 n. 8, p. article no. 129918-
dc.identifier.issn0304-4165-
dc.identifier.urihttp://hdl.handle.net/10722/300841-
dc.description.abstractBackground: Recently, through comprehensive medicinal chemistry efforts, we have found a new daptomycin analogue, termed kynomycin, showing enhanced activity against both methicillin-resistant S. aureus and vancomycin-resistant Enterococcus in vitro and in vivo, with improved pharmacokinetics and lower cytotoxicity than daptomycin. Methods: In this study we compared the physicochemical properties of kynomycin with those of daptomycin from an atomic perspective by using Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations. Results and conclusion: We observed that kynurenine methylation changes daptomycin’s key physicochemical properties; its calcium dependent oligomerization efficiency is improved and the modified kynurenine strengths contacts with the lipid tail and tryptophan residues. In addition, it is observed that, compared to daptomycin, kynomycin tetramer is more stable and binds stronger to calcium. The combined experiments provide key clues for the improved antibacterial activity of kynomycin. General significance: We expect that this approach will help study the calcium binding and oligomerization features of new calcium dependent peptide antibiotics.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/issn/03044165-
dc.relation.ispartofBiochimica et Biophysica Acta (BBA) - General Subjects-
dc.subjectDaptomycin-
dc.subjectCalcium dependent antibiotics-
dc.subjectOligomerization-
dc.subjectNuclear magnetic resonance (NMR)-
dc.subjectMolecular dynamics (MD)-
dc.titleAn atomic perspective on improving daptomycin’s activity-
dc.typeArticle-
dc.identifier.emailBlasco Morales, P: pbmoral@hku.hk-
dc.identifier.emailChow, HY: hchowhy@connect.hku.hk-
dc.identifier.emailChen, G: ghchen@hku.hk-
dc.identifier.emailLi, X: xuechenl@hku.hk-
dc.identifier.authorityChen, G=rp00671-
dc.identifier.authorityLi, X=rp00742-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.bbagen.2021.129918-
dc.identifier.pmid33965439-
dc.identifier.scopuseid_2-s2.0-85105803894-
dc.identifier.hkuros323092-
dc.identifier.volume1865-
dc.identifier.issue8-
dc.identifier.spagearticle no. 129918-
dc.identifier.epagearticle no. 129918-
dc.publisher.placeNetherlands-

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