Symmetry Requirements for Effective Blocking of Pore-Forming Toxins: Comparative Study with α-, β-, and γ-Cyclodextrin Derivatives

We compared the abilities of structurally related cationic cyclodextrins to inhibit Bacillus anthracis lethal toxin and Staphylococcus aureus alpha-hemolysin. We found that both beta- and gamma-cyclodextrin derivatives effectively inhibited anthrax toxin action by blocking the transmembrane oligomeric pores formed by the protective antigen (PA) subunit of the toxin, whereas alpha-cyclodextrins were ineffective. In contrast, alpha-hemolysin was selectively blocked only by beta-cyclodextrin derivatives, demonstrating that both symmetry and size of the inhibitor and the pore are important.