PXD050156

PXD050156 is an original dataset announced via ProteomeXchange.

Title	Highly potent quinoxalinediones inhibit α−hemolysin and ameliorate lung infections by Staphylococcus aureus
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-03-05
AnnouncementXML	Submission_2025-03-05_06:02:51.430.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lothar Jaensch
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	methylthiolated residue; monohydroxylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-02-26 10:20:28	ID requested
⏵ 1	2025-03-05 06:02:51	announced

Dataset with its publication pending

submitter keyword: pathoblocker, S. aureus, antibacterial,alpha-hemolysin

Lothar Jaensch
contact affiliation	Cellular Proteomics Group Helmholtz Centre for Infection Research Inhoffenstr. 7 38124 Braunschweig Germany
contact email	Lothar.Jaensch@Helmholtz-hzi.de
lab head
Lothar Jaensch
contact affiliation	HZI
contact email	Lothar.Jaensch@Helmholtz-HZI.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050156
     1. Label: PRIDE project
     2. Name: Highly potent quinoxalinediones inhibit α−hemolysin and ameliorate lung infections by Staphylococcus aureus