PXD012946 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
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. |
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 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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD012946
- Label: PRIDE project
- Name: Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus