Highly potent quinoxalinediones inhibit α-hemolysin and ameliorate Staphylococcus aureus lung infections

Cell Host Microbe. 2025 Apr 9;33(4):560-572.e21. doi: 10.1016/j.chom.2025.03.006.

Aditya Shekhar ¹, Raffaella Di Lucrezia ², Karoline Jerye ³, Vadim S Korotkov ³, Kirsten Harmrolfs ³, Katharina Rox ⁴, Herbert A Weich ³, Ishan Ghai ⁵, Florent Delhommel ⁶, Isabelle Becher ⁷, Carsten Degenhart ², Eyad Fansa ², Anke Unger ², Peter Habenberger ², Bert Klebl ², Peer Lukat ⁸, Stefan Schmelz ⁸, Steffi Henke ⁸, Sebastian Borgert ⁸, Julia C Lang ⁹, Florenz Sasse ³, Randi Diestel ³, Clémentine Richter ¹⁰, Nicole Schneider-Daum ¹¹, Bettina Hinkelmann ³, Jana Niemz ¹², Claus-Michael Lehr ¹⁰, Lothar Jänsch ¹³, Jochen Huehn ¹⁴, Richard Alm ¹⁵, Mikhail Savitski ⁷, Tobias Welte ¹⁶, Thomas Hesterkamp ¹⁷, Michael Sattler ⁶, Mathias Winterhalter ⁵, Wulf Blankenfeldt ⁸, Eva Medina ⁹, Ursula Bilitewski ¹, Klaus Dinkel ², Mark Brönstrup ¹⁸

Affiliations

1 Compound Profiling and Screening, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
2 Lead Discovery Center, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.
3 Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
4 Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany; German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Braunschweig, Germany.
5 Life Sciences and Chemistry, Constructor University, 28759 Bremen, Germany.
6 Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience, Bavarian NMR Center, Lichtenbergstrasse 4, 85747 Garching, Germany; Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
7 Proteomics Core Facility, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
8 Structure and Function of Proteins, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
9 Infection Immunology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
10 Department of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research (HIPS), Campus E8.1, 66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
11 Department of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research (HIPS), Campus E8.1, 66123 Saarbrücken, Germany.
12 Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
13 Cellular Proteomics, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
14 Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany; Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
15 CARB-X, Boston, MA, USA.
16 Department of Respiratory Medicine and Infectious Disease, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover 30625, Germany.
17 German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Braunschweig, Germany.
18 Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany; German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Braunschweig, Germany; Center of Biomolecular Drug Research (BMWZ), Leibniz Universität, 30167 Hannover, Germany. Electronic address: mark.broenstrup@helmholtz-hzi.de.

PMID: 40168998 DOI: 10.1016/j.chom.2025.03.006

Abstract

Hospital-acquired pneumonia caused by Staphylococcus aureus is associated with patient morbidity and mortality, despite adequate Antibiotic therapy. This illustrates the need for treatments beyond Antibiotics. The pore-forming heptameric toxin α-hemolysin (Hla) is a major pathogenicity factor of S. aureus and a clinically validated target. We identify quinoxalinediones (QDS) as highly potent Hla inhibitors, conferring protection against the hallmarks of Hla-induced pathogenicity such as CA²⁺ influx, cytotoxicity, hemolysis, and monolayer destruction. The effects were exerted across major Hla subtypes in all relevant cell types. QDS prevented the formation of functional pores by interacting with Hla near the phospholipid-binding site. The QDS analog, H052, was active in mouse models of S. aureus lung infections, when administered prophylactically or therapeutically, either as monotherapy or when given in combination with the Antibiotic linezolid. The study provides evidence that complex Bacterial toxins can be targeted in vivo by drug-like small molecules.

Keywords

Staphylococcus aureus; antibacterials; drug discovery; lung infections; mechanism of action; toxin inhibition; virulence inhibitors.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-173526

H052

Hla Inhibitor

Bacterial; Calcium Channel

Infection

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