9SHR

Alpha-Hemolysin of S.aureus (monomer) in complex with the small molecule N-(3-(Diethylamino)propyl)-1-(6-(p-tolyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide

This is a non-PDB format compatible entry.

Summary for 9SHR

• Entry DOI: 10.2210/pdb9shr/pdb
• Descriptor: Alpha-hemolysin, ~{N}-[3-(diethylamino)propyl]-1-[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidine-4-carboxamide, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (6 entities in total)
• Functional Keywords: alpha-hemolysin, hla, cytolysin, pore-forming toxin, mrsa, pathoblocker, toxin
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 36290.01

Authors

Lukat, P.,Blankenfeldt, W.,Broenstrup, M. (deposition date: 2025-08-27, release date: 2026-03-04)

Primary citation

Korotkov, V.S.,Lukat, P.,Di Lucrezia, R.,Shekhar, A.,Degenhart, C.,Diestel, R.,Bilitewski, U.,Dinkel, K.,Blankenfeldt, W.,Bronstrup, M.
An Imidazo[2,1-b][1,3,4]thiadiazole Derivative Inhibits the Virulence Factor alpha-Hemolysin by Blocking the Pullout of Its Stem Domain.
Chemmedchem, 21:e202501098-e202501098, 2026

PubMed Abstract: Staphylococcus aureus is a major human pathogen responsible for severe infections that necessitate alternative therapeutic strategies. Its key virulence factor α-hemolysin (Hla) mediates host cell damage via pore formation, making it an attractive target for antivirulence interventions. Here, we report the development of a high-throughput cellular assay measuring toxin-induced calcium influx. Its application led to the identification of thiadiazole-based small molecule inhibitors of Hla. Structure-activity relationship studies with 18 analogs led to inhibitors with a cellular potency up to 5.4 µM. X-ray crystallography of Hla in complex with compound 1 revealed that the thiadiazole bound a hydrophobic pocket at the interface of the amino latch and prestem domains, exerting a dual mechanism that blocks stem loop unfolding as well as membrane attachment. These findings introduce thiadiazoles as a novel chemical class of antivirulence therapeutics against S. aureus infections.

PubMed: 41725408
DOI: 10.1002/cmdc.202501098

Experimental method

X-RAY DIFFRACTION (2.08 Å)