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

ABSTRACT: Hospital-acquired pneumonia caused by Staphylococcus aureus is associated with patient morbidity and mortality, in spite of adequate antibiotic therapy. Therefore, there is a need for novel treatment concepts that go beyond antibiotics. The pore-forming heptameric toxin α-hemolysin (Hla) is a major pathogenicity factor of S. aureus and a clinically validated target. Using Hla-dependent phenotypic cellular assays, we discovered quinoxalinediones (QDS) as highly potent Hla inhibitors. QDS reverted the hallmarks of Hla pathogenicity by conferring protection against Hla-induced Ca2+ influx, cytotoxicity, hemolysis, and by maintaining monolayer integrity of lung epithelial cells. The cellular effects were exerted in the nM range across all major Hla subtypes and shown in relevant cell types, including lung epithelial and endothelial cells, and primary human immune cells. QDS prevented the formation of functional pores by interacting with Hla monomers. Structural data by NMR and chemoproteomics showed monomer binding near the phospholipid binding site of the protein, a functional site required for membrane integration. The analog H052 was active in mouse models of S. aureus lung infections in pre-emptive and therapeutic settings, as a monotherapy and in combination with subtherapeutic doses of linezolid. The QDS provide first evidence that of large bacterial toxins can be effectively inhibited by drug-like small molecules. The virulence-attenuating drug candidate may now be developed as a monotherapy in a pre-emptive intervention setting.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Lothar Jaensch  

LAB HEAD: Lothar Jaensch

PROVIDER: PXD050156 | Pride | 2025-03-05

REPOSITORIES: Pride