Characterization of the Interaction of Daptomycin with Site II on Human Serum Albumin

Keishi Yamasaki, Keiki Sakurama, Koji Nishi, Hiroshi Watanabe, Toru Maruyama, Hakaru Seo, Masaki Otagiri, Kazuaki Taguchi

Research output: Contribution to journalArticle

Abstract

Daptomycin, a cyclic lipopeptide antibiotic, is clinically used for the treatment of infections caused by Gram-positive bacteria, including the methicillin-resistant Staphylococcus aureus and the vancomycin-resistant Enterococci. While daptomycin shows high plasma protein binding (90–93%), our knowledge of the binding process is not extensive. To address this issue in more detail, we characterized the binding of daptomycin to plasma proteins and the findings indicate that the association constant for the binding of daptomycin to human serum albumin (HSA) is much higher than that for α1-acid glycoprotein, another plasma protein. Daptomycin was also found to bind to a single site on HSA, which was identified as site II. The findings also suggest that the n-decanoyl moiety of daptomycin penetrates into the hydrophobic pocket of site II and that this acyl moiety interacts with Tyr411 at the entrance to site II. Due to this selective interaction with site II, daptomycin binding was significantly inhibited by drugs (ibuprofen or diazepam) and endogenous compounds (uremic toxins or fatty acids) which also strongly bind to site II. In diseased states, such an inhibition in the binding could result in the pharmacokinetics and therapeutic action of daptomycin being substantially altered.

Original languageEnglish
JournalJournal of Pharmaceutical Sciences
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • Binding site
  • Daptomycin
  • Human serum albumin
  • Protein binding
  • Site II

ASJC Scopus subject areas

  • Pharmaceutical Science

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