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PXD012946

PXD012946 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleRepurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus
DescriptionTo 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.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_04:54:01.742.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterPhilipp Le
SpeciesList scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationListdimethylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion ETD; Q Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02019-03-04 02:16:32ID requested
12019-09-11 11:48:31announced
22020-01-10 02:00:09announced2020-01-10: Updated publication reference for PubMed record(s): 31844194.
32024-10-22 04:54:03announced2024-10-22: Updated project metadata.
Publication List
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]
Keyword List
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
Contact List
Stephan A. Sieber
contact affiliationCenter 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 emailstephan.sieber@tum.de
lab head
Philipp Le
contact affiliationTechnische Universität München Department of Chemistry Sieber Lab | Prof. Dr. Stephan A. Sieber Lichtenbergstraße 4 D-85748 Garching Germany
contact emailphilipp.le@tum.de
dataset submitter
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