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dc.contributor.authorSchneider, Elena K
dc.contributor.authorHuang, Johnny X
dc.contributor.authorCarbone, Vincenzo
dc.contributor.authorHan, Meiling
dc.contributor.authorZhu, Yan
dc.contributor.authorNang, Sue
dc.contributor.authorKhoo, Keith K
dc.contributor.authorMak, Johnson
dc.contributor.authorCooper, Matthew A
dc.contributor.authorLi, Jian
dc.contributor.authorVelkov, Tony
dc.date.accessioned2021-06-25T06:03:22Z
dc.date.available2021-06-25T06:03:22Z
dc.date.issued2017
dc.identifier.issn2373-8227
dc.identifier.doi10.1021/acsinfecdis.7b00015
dc.identifier.urihttp://hdl.handle.net/10072/405381
dc.description.abstractDaptomycin is a lipopeptide antibiotic that is highly bound to plasma proteins. To date, the plasma components and structure–activity relationships responsible for the plasma protein binding profile of daptomycin remain uncharacterized. In the present study we have employed a surface plasmon resonance assay together with molecular docking techniques to investigate the plasma protein binding structure–activity relationships related to the N-terminal fatty acyl of daptomycin. Three compounds were investigated: (1) native daptomycin, which displays an N-terminal n-decanoyl fatty acid side chain, and two analogues with modifications to the N-terminal fatty acyl chain; (2) des-acyl daptomycin; and (3) acetyl-daptomycin. The surface plasmon resonance (SPR) data showed that the binding profile of native daptomycin was in the rank order human serum albumin (HSA) ≫ α-1-antitrypsin > low-density lipoprotein ≥ hemoglobin > sex hormone binding globulin > α-1-acid-glycoprotein (AGP) > hemopexin > fibrinogen > α-2-macroglobulin > β2-microglobulin > high-density lipoprotein > fibronectin > haptoglobulin > transferrin > immunoglobulin G. Notably, binding to fatty acid free HSA was greater than binding to nondelipidated HSA. SPR and ultrafiltration studies also indicated that physiological concentrations of calcium increase binding of daptomycin and acetyl-daptomycin to HSA and AGP. A molecular model of the daptomycin–human serum albumin A complex is presented that illustrates the pivotal role of the N-terminal fatty acyl chain of daptomycin for binding to drug site 1 of HSA. In proof-of-concept, the capacity of physiological cocktails of the identified plasma proteins to inhibit the antibacterial activity of daptomycin was assessed with in vitro microbiological assays. We show that HSA, α-1-antitrypsin, low-density lipoprotein, sex hormone binding globulin, α-1-acid-glycoprotein, and hemopexin are responsible for the majority of the sequestering activity in human plasma. The findings are relevant to medicinal chemistry programs focused on the development of next-generation daptomycin lipopeptides. Tailored modifications to the N-terminal fatty acyl domain of the daptomycin molecule should yield novel daptomycin lipopeptides with more ideal plasma protein binding profiles to increase the levels of active (free) drug in plasma and improved in vivo activity.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherAmerican Chemical Society
dc.relation.ispartofpagefrom249
dc.relation.ispartofpageto258
dc.relation.ispartofissue3
dc.relation.ispartofjournalACS Infectious Diseases
dc.relation.ispartofvolume3
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedical Microbiology
dc.subject.fieldofresearchcode0605
dc.subject.fieldofresearchcode1108
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsChemistry, Medicinal
dc.subject.keywordsInfectious Diseases
dc.subject.keywordsPharmacology & Pharmacy
dc.titlePlasma protein binding structure–activity relationships related to the N-terminus of daptomycin
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationSchneider, EK; Huang, JX; Carbone, V; Han, M; Zhu, Y; Nang, S; Khoo, KK; Mak, J; Cooper, MA; Li, J; Velkov, T, Plasma protein binding structure–activity relationships related to the N-terminus of daptomycin, ACS Infectious Diseases, 2017, 3 (3), pp. 249-258
dc.date.updated2021-06-25T05:55:46Z
gro.hasfulltextNo Full Text
gro.griffith.authorMak, Johnson


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