<p>Cholesterol-dependent cytolysins (CDCs)
are proteinaceous toxins secreted as monomers by some Gram-positive and
Gram-negative bacteria that contribute to their pathogenicity. These toxins
bind to either cholesterol or human CD59, leading to massive structural changes,
toxin oligomerization, formation of very large pores, and ultimately cell death,
making these proteins promising targets for inhibition. Myricetin, and its
related flavonoids, have been previously identified as a candidate small
molecule inhibitor of specific CDCs such as listeriolysin O (LLO) and suilysin
(SLY), interfering with their oligomerization. In this work, molecular docking
was performed to assess the interaction of myricetin with other CDCs whose
crystal structures are already known. Results indicated that although myricetin
bound to the hitherto identified cavity in domain 4 (D4), much more efficient
and stable binding was obtained in sites along the interfacial regions of
domains 1 – 3 (D1 – D3). This was common among the tested CDCs, which was primarily
due to much more extensive stabilizing intermolecular interactions, as
indicated by post-docking analysis. Specifically, myricetin bound to (1) the
interface of the three domains in anthrolysin O (ALO), perfringolysin O (PFO),
pneumolysin (PLY), SLY, and vaginolysin (VLY), (2) at/near the D1/D3 interface
in LLO and streptolysin O (SLO), and (3) along the D2/D3 interface in
intermedilysin (ILY). These findings provide theoretical basis on the
possibility of using myricetin and its related compounds as a broad-spectrum
inhibitor of CDCs to potentially address the diseases associated with these pathogens.</p>
Effect of zinc ion on the hemolytic activity of thermostable direct hemolysin from Vibrio parahaemolyticus, streptolysin O, and Triton X-100.
