Nature communications, 2024-04, Vol.15 (1), p.3537-3537, Article 3537
2024
Details
- Autor(en) / Beteiligte
- Titel
- Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins
- Ist Teil von
- Nature communications, 2024-04, Vol.15 (1), p.3537-3537, Article 3537
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2024
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Pneumolysin (PLY) is a cholesterol-dependent cytolysin (CDC) from Streptococcus pneumoniae, the main cause for bacterial pneumonia. Liberation of PLY during infection leads to compromised immune system and cytolytic cell death. Here, we report discovery, development, and validation of targeted small molecule inhibitors of PLY (pore-blockers, PB). PB-1 is a virtual screening hit inhibiting PLY-mediated hemolysis. Structural optimization provides PB-2 with improved efficacy. Cryo-electron tomography reveals that PB-2 blocks PLY-binding to cholesterol-containing membranes and subsequent pore formation. Scaffold-hopping delivers PB-3 with superior chemical stability and solubility. PB-3, formed in a protein-templated reaction, binds to Cys428 adjacent to the cholesterol recognition domain of PLY with a K of 256 nM and a residence time of 2000 s. It acts as anti-virulence factor preventing human lung epithelial cells from PLY-mediated cytolysis and cell death during infection with Streptococcus pneumoniae and is active against the homologous Cys-containing CDC perfringolysin (PFO) as well.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-024-47741-3Titel-ID: cdi_doaj_primary_oai_doaj_org_article_d115b78ddffa4616af6f6aa528f3f42c
- Format
- –
- Schlagworte
- A549 Cells, Antibiotics, Bacteria, Bacterial Proteins - antagonists & inhibitors, Bacterial Proteins - chemistry, Bacterial Proteins - metabolism, Bacterial Toxins - antagonists & inhibitors, Bacterial Toxins - chemistry, Bacterial Toxins - metabolism, Cell death, Cholesterol, Cholesterol - metabolism, Cryoelectron Microscopy, Cytolysis, Epithelial cells, Epithelial Cells - drug effects, Epithelial Cells - metabolism, Epithelium, Hemolysin Proteins - chemistry, Hemolysin Proteins - metabolism, Hemolysis - drug effects, Homology, Humans, Immune system, Inhibitors, Pneumolysin, Pneumonia, Pore formation, Small Molecule Libraries - chemistry, Small Molecule Libraries - pharmacology, Streptococcus infections, Streptococcus pneumoniae, Streptococcus pneumoniae - drug effects, Streptolysins - chemistry, Streptolysins - metabolism, Toxins, Virulence, Virulence factors, Virulence Factors - metabolism