Highly potent quinoxalinediones inhibit α-hemolysin and ameliorate Staphylococcus aureus lung infections
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 Ca<sup>2+</sup> 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.
Authors
- Florenz Sasse (ORCID: https://orcid.org/0000-0002-6437-7742)
- Mikhail M. Savitski (ORCID: https://orcid.org/0000-0003-2011-9247)
- Wulf Blankenfeldt (ORCID: https://orcid.org/0000-0001-9886-9668)
- Bert Klebl (ORCID: https://orcid.org/0000-0001-5475-9053)
- Peter Habenberger (ORCID: https://orcid.org/0000-0002-1251-264X)
- Jana Niemz
- Stefan Schmelz (ORCID: https://orcid.org/0000-0002-2511-7593)
- Ursula Bilitewski (ORCID: https://orcid.org/0000-0003-2952-1208)
- Carsten Degenhart
- Anke Unger (ORCID: https://orcid.org/0000-0003-1288-3763)
- Bettina Hinkelmann
- Jochen Huehn (ORCID: https://orcid.org/0000-0001-8071-1379)
- Kirsten Harmrolfs (ORCID: https://orcid.org/0000-0001-5648-0750)
- Ishan Ghai (ORCID: https://orcid.org/0000-0003-3713-403X)
- Nicole Schneider‐Daum (ORCID: https://orcid.org/0000-0001-9319-2010)
- Mark Brönstrup (ORCID: https://orcid.org/0000-0002-8971-7045)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Michael Sattler (ORCID: https://orcid.org/0000-0002-1594-0527)
- Randi Diestel
- Peer Lukat (ORCID: https://orcid.org/0000-0001-9897-3430)
- Aditya Shekhar (ORCID: https://orcid.org/0000-0001-7383-6050)
- Tobias Welte (ORCID: https://orcid.org/0000-0002-9947-7356)
- Klaus Dinkel
- Richard A. Alm (ORCID: https://orcid.org/0000-0002-5056-7377)
- Isabelle Becher (ORCID: https://orcid.org/0000-0001-7170-2235)
- Clémentine Richter (ORCID: https://orcid.org/0000-0001-6304-7242)
- Sebastian Borgert (ORCID: https://orcid.org/0000-0002-7140-1907)
- Julia C. Lang (ORCID: https://orcid.org/0000-0001-7641-2472)
- S. Henke (ORCID: https://orcid.org/0000-0001-7446-5554)
- Eva Medina (ORCID: https://orcid.org/0000-0002-5935-3260)
- Raffaella Di Lucrezia (ORCID: https://orcid.org/0000-0001-6510-9945)
- Mathias Winterhalter (ORCID: https://orcid.org/0000-0002-1604-3318)
- Florent Delhommel (ORCID: https://orcid.org/0000-0001-7021-087X)
- Lothar Jänsch (ORCID: https://orcid.org/0000-0002-5655-1181)
- Vadim S. Korotkov (ORCID: https://orcid.org/0000-0003-3970-2483)
- Karoline Jerye
- Thomas Hesterkamp (ORCID: https://orcid.org/0000-0002-2539-9068)
- Herbert A. Weich
- Claus‐Michael Lehr (ORCID: https://orcid.org/0000-0002-5864-8462)
- Eyad Fansa
Institutions
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.chom.2025.03.006
- Citations
- 9
- Primary Topic
- Synthesis and Biological Evaluation
- Type
- article
- Field-Weighted Citation Impact
- 8.42