Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins

Umer Bin Abdul Aziz, Ali Saoud, Marcel Bermudez, Maren Mieth, Amira Atef, Thomas Rudolf, Christoph Arkona, Timo Trenkner, Christoph Böttcher, Kai Ludwig, Angelique Hoelzemer, Andreas C. Hocke, Gerhard Wolber and Jörg Rademann ()
Additional contact information
Umer Bin Abdul Aziz: Freie Universität Berlin
Ali Saoud: Freie Universität Berlin
Marcel Bermudez: Freie Universität Berlin
Maren Mieth: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Amira Atef: Freie Universität Berlin
Thomas Rudolf: Freie Universität Berlin
Christoph Arkona: Freie Universität Berlin
Timo Trenkner: Leibniz Institute of Virology
Christoph Böttcher: Freie Universität Berlin
Kai Ludwig: Freie Universität Berlin
Angelique Hoelzemer: Leibniz Institute of Virology
Andreas C. Hocke: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Gerhard Wolber: Freie Universität Berlin
Jörg Rademann: Freie Universität Berlin

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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 KD 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-47741-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47741-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-47741-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().