Inhibition of S. aureus α-hemolysin and B. anthracis lethal toxin by β-cyclodextrin derivatives

Vladimir A. Karginov, Ekaterina M. Nestorovich, Frank Schmidtmann, Tanisha M. Robinson, Adiamseged Yohannes, Nour Eddine Fahmi, Sergey M. Bezrukov, Sidney M. Hecht

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Many pathogens utilize the formation of transmembrane pores in target cells in the process of infection. A great number of pore-forming proteins, both bacterial and viral, are considered to be important virulence factors, which makes them attractive targets for the discovery of new therapeutic agents. Our research is based on the idea that compounds designed to block the pores can inhibit the action of virulence factors, and that the chances to find high affinity blocking agents increase if they have the same symmetry as the target pore. Recently, we demonstrated that derivatives of β-cyclodextrin inhibited anthrax lethal toxin (LeTx) action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. To test the broader applicability of this approach, we sought β-cyclodextrin derivatives capable of inhibiting the activity of Staphylococcus aureus α-hemolysin (α-HL), which is regarded as a major virulence factor playing an important role in staphylococcal infection. We identified several amino acid derivatives of β-cyclodextrin that inhibited the activity of α-HL and LeTx in cell-based assays at low micromolar concentrations. One of the compounds was tested for the ability to block ion conductance through the pores formed by α-HL and PA in artificial lipid membranes. We anticipate that this approach can serve as the basis for a structure-directed drug discovery program to find new and effective therapeutics against various pathogens that utilize pore-forming proteins as virulence factors.

Original languageEnglish (US)
Pages (from-to)5424-5431
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number16
DOIs
StatePublished - Aug 15 2007
Externally publishedYes

Keywords

  • Anthrax toxin
  • Inhibitors
  • Staphylococcus aureus
  • α-Hemolysin
  • β-Cyclodextrin derivatives

ASJC Scopus subject areas

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

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  • Cite this

    Karginov, V. A., Nestorovich, E. M., Schmidtmann, F., Robinson, T. M., Yohannes, A., Fahmi, N. E., Bezrukov, S. M., & Hecht, S. M. (2007). Inhibition of S. aureus α-hemolysin and B. anthracis lethal toxin by β-cyclodextrin derivatives. Bioorganic and Medicinal Chemistry, 15(16), 5424-5431. https://doi.org/10.1016/j.bmc.2007.05.058