Plasma protein binding structure activity relationships related to the N-terminus of daptomycin

Schneider, Elena K., Huang, Johnny X., Carbone, Vincenzo, Han, Meiling, Zhu, Yan, Nang, Sue, Khoo, Keith K., Mak, Johnson, Cooper, Matthew A., Li, Jian and Velkov, Tony (2017) Plasma protein binding structure activity relationships related to the N-terminus of daptomycin. ACS Infectious Diseases, 3 3: 249-258. doi:10.1021/acsinfecdis.7b00015

Author Schneider, Elena K.
Huang, Johnny X.
Carbone, Vincenzo
Han, Meiling
Zhu, Yan
Nang, Sue
Khoo, Keith K.
Mak, Johnson
Cooper, Matthew A.
Li, Jian
Velkov, Tony
Title Plasma protein binding structure activity relationships related to the N-terminus of daptomycin
Journal name ACS Infectious Diseases   Check publisher's open access policy
ISSN 2373-8227
Publication date 2017-03-10
Year available 2017
Sub-type Article (original research)
DOI 10.1021/acsinfecdis.7b00015
Open Access Status Not yet assessed
Volume 3
Issue 3
Start page 249
End page 258
Total pages 10
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
Subject 2725 Infectious Diseases
Abstract Daptomycin 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.
Keyword Daptomycin
Plasma protein binding
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1064896
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Mon, 17 Apr 2017, 01:00:48 EST by Web Cron on behalf of Institute for Molecular Bioscience