PXD012946

PXD012946 is an original dataset announced via ProteomeXchange.

Title	Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus
Description	To combat methicillin-resistant Staphylococcus aureus (MRSA) infections novel drugs are desperately needed. From a screen, we found that the anti-cancer drug sorafenib effectively kills MRSA strains. By synthetic variation of key structural features, we identified a potent analog, PK150, exhibiting activities against several pathogenic strains at sub-micromolar concentrations. The antibiotic induced rapid killing of S. aureus, including challenging persisters, and eradicated established biofilms. PK150 holds promising therapeutic potential as it did not induce in vitro resistance and exhibited oral bioavailability and in vivo efficacy. Mode of action analysis by chemical proteomics revealed several targets, including interference with menaquinone biosynthesis by inhibiting demethylmenaquinone methyltransferase and stimulation of protein secretion by altering the activity of signal peptidase IB. Reduced endogenous menaquinone levels along with enhanced levels of extracellular proteins of PK150-treated bacteria support this hypothesis. The associated antibiotic effects, especially the lack of resistance development, likely stem from the compound’s polypharmacology attribute.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:54:01.742.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Philipp Le
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	dimethylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion ETD; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-03-04 02:16:32	ID requested
1	2019-09-11 11:48:31	announced
2	2020-01-10 02:00:09	announced	2020-01-10: Updated publication reference for PubMed record(s): 31844194.
⏵ 3	2024-10-22 04:54:03	announced	2024-10-22: Updated project metadata.

10.1038/s41557-019-0378-7;

Le P, Kunold E, Macsics R, Rox K, Jennings MC, Ugur I, Reinecke M, Chaves-Moreno D, Hackl MW, Fetzer C, Mandl FAM, Lehmann J, Korotkov VS, Hacker SM, Kuster B, Antes I, Pieper DH, Rohde M, Wuest WM, Medina E, Sieber SA, Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms. Nat Chem, 12(2):145-158(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: full proteome, affinity-based protein profiling (AfBPP), Q Exactive Plus,chemical proteomics, Staphylococcus aureus subsp. aureus NCTC 8325, secretome, surfaceome, Orbitrap Fusion

Stephan A. Sieber
contact affiliation	Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Garching b. München 85747, Germany; Chair of Organic Chemistry II, Technische Universität München, Garching b. München 85747, Germany
contact email	stephan.sieber@tum.de
lab head
Philipp Le
contact affiliation	Technische Universität München Department of Chemistry Sieber Lab | Prof. Dr. Stephan A. Sieber Lichtenbergstraße 4 D-85748 Garching Germany
contact email	philipp.le@tum.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/09/PXD012946

PRIDE project URI

• PRIDE
  1. PXD012946
     1. Label: PRIDE project
     2. Name: Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus