The effect of the placement and total charge of the basic amino acid clusters on antibacterial organism selectivity and potency

Amanda L. Russell, Anne M. Spuches, Brittany C. Williams, Divakaramenon Venugopal, David Klapper, Antoine H. Srouji, Rickey P. Hicks

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Extensive circular dichroism, isothermal titration calorimetry and induced calcein leakage studies were conducted on a series of antimicrobial peptides (AMPs), with a varying number of Lys residues located at either the C-terminus or the N-terminus to gain insight into their effect on the mechanisms of binding with zwitterionic and anionic membrane model systems. Different CD spectra were observed for these AMPs in the presence of zwitterionic DPC and anionic SDS micelles indicating that they adopt different conformations on binding to the surfaces of zwitterionic and anionic membrane models. Different CD spectra were observed for these AMPs in the presence of zwitterionic POPC and anionic mixed 4:1 POPC/POPG LUVs and SUVs, indicating that they adopt very different conformations on interaction with these two types of LUVs and SUVs. In addition, ITC and calcein leakage data indicated that all the AMPs studied interact via very different mechanisms with anionic and zwitterionic LUVs. ITC data suggest these peptides interact primarily with the surface of zwitterionic LUVs while they insert into and form pores in anionic LUVs. CD studies indicated that these compounds adopt different conformations depending on the ratio of POPC to POPG lipids present in the liposome. There are detectable spectroscopic and thermodynamic differences between how each of these AMPs interacts with membranes, that is position and total charge density defines how these AMPs interact with specific membrane models and thus partially explain the resulting diversity of antibacterial activity of these compounds.

Original languageEnglish (US)
Pages (from-to)7008-7022
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number23
DOIs
StatePublished - Dec 1 2011

Keywords

  • Antimicrobial peptides
  • CD spectroscopy
  • Calcein leakage
  • Fluorescence spectroscopy
  • Isothermal titration calorimetry
  • Unnatural amino acids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Russell, A. L., Spuches, A. M., Williams, B. C., Venugopal, D., Klapper, D., Srouji, A. H., & Hicks, R. P. (2011). The effect of the placement and total charge of the basic amino acid clusters on antibacterial organism selectivity and potency. Bioorganic and Medicinal Chemistry, 19(23), 7008-7022. https://doi.org/10.1016/j.bmc.2011.10.033