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Published on: September 30, 2014
Inhibition of Pneumolysin Cytotoxicity by Hydrolysable Tannins
Santeri Maatsola1, Sami Kurkinen2, Marica T Engström3,4
1Institute of Biomedicine, Research Center for Cancer, Infections and Immunity, University of Turku, 20014 Turku, Finland.
Abstract:
Streptococcus pneumoniae causes invasive infections such as otitis media, pneumonia and meningitis. It produces the pneumolysin (Ply) toxin, which forms a pore onto the host cell membrane and has multiple functions in the pathogenesis of S. pneumoniae. The Ply C-terminal domain 4 mediates binding to membrane cholesterol and induces the formation of pores composed of up to 40 Ply monomers. Ply has a key role in the establishment of nasal colonization, pneumococcal transmission from host to host and pathogenicity. Altogether, 27 hydrolysable tannins were tested for Ply inhibition in a hemolysis assay and a tannin-protein precipitation assay. Pentagalloylglucose (PGG) and gemin A showed nanomolar inhibitory activity. Ply oligomerization on the erythrocyte surface was inhibited with PGG. PGG also inhibited Ply cytotoxicity to A549 human lung epithelial cells. Molecular modelling of Ply interaction with PGG suggests that it binds to the pocket formed by domains 2, 3 and 4. In this study, we reveal the structural features of hydrolysable tannins that are required for interaction with Ply. Monomeric hydrolysable tannins containing three to four flexible galloyl groups have the highest inhibitory power to Ply cytotoxicity and are followed by oligomers. Of the oligomers, macrocyclic and C-glycosidic structures were weaker in their inhibition than the glucopyranose-based oligomers. Accordingly, PGG-type monomers and oligomers might have therapeutic value in the targeting of S. pneumoniae infections.
Insights
Pentagalloylglucose (PGG) and similar tannins inhibit pneumolysin (Ply), a toxin from Streptococcus pneumoniae. These compounds show potential for treating pneumococcal infections by blocking Ply
Area of Science:
- Microbiology
- Toxicology
- Biochemistry
Background:
- Streptococcus pneumoniae causes invasive infections like pneumonia and meningitis.
- Pneumolysin (Ply) is a key toxin produced by S. pneumoniae, forming pores in host cell membranes and contributing to disease.
- Ply's C-terminal domain 4 binds cholesterol, facilitating pore formation by up to 40 Ply monomers.
Purpose of the Study:
- To identify hydrolysable tannins that inhibit pneumolysin (Ply) activity.
- To elucidate the structural features of tannins required for Ply inhibition.
- To explore the therapeutic potential of Ply inhibitors against S. pneumoniae infections.
Main Methods:
- Hemolysis and tannin-protein precipitation assays were used to screen 27 hydrolysable tannins for Ply inhibition.
- Cytotoxicity assays with A549 lung epithelial cells were performed.
- Molecular modeling was employed to study the interaction between Ply and Pentagalloylglucose (PGG).
Main Results:
- Pentagalloylglucose (PGG) and gemin A exhibited nanomolar inhibitory activity against Ply.
- PGG effectively inhibited Ply oligomerization on erythrocytes and Ply-induced cytotoxicity to A549 cells.
- Monomeric hydrolysable tannins with three to four flexible galloyl groups showed the highest inhibitory activity, followed by glucopyranose-based oligomers.
Conclusions:
- Hydrolysable tannins, particularly PGG-type monomers and oligomers, can effectively inhibit pneumolysin.
- The structural features of tannins, such as the number and flexibility of galloyl groups, are crucial for Ply inhibition.
- PGG and related compounds represent promising therapeutic agents for targeting Streptococcus pneumoniae infections.
