PXD008070-1

PXD008070 is an original dataset announced via ProteomeXchange.

Title	Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms
Description	To combat methicillin-resistant Staphylococcus aureus (MRSA) infections novel drugs addressing unprecedented and resistance-free targets are desperately needed. From a screen of human kinase inhibitors, we find that the anti-cancer drug sorafenib effectively kills MRSA strains. By dissection of the sorafenib scaffold and systematic synthesis of 72 analogs, we identify a potent compound – PK150 – exhibiting a minimal inhibitory concentration of 300 nM against several MRSA strains. 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 good oral bioavailability and in vivo efficacy in a mouse infection model. Mode of action analysis by chemical proteomics revealed several targets including stimulation of protein secretion by signal peptidase IB (SpsB). Enhanced levels of extracellular proteins and resulting imbalances in secreted autolysin levels of PK150-treated bacteria support this target hypothesis. The associated antibiotic effects, especially the lack of resistance development, likely stem from the polypharmacology attribute of the compound. PK150 is therefore the founding member of a new class of highly active antibiotics.
HostingRepository	PRIDE
AnnounceDate	2022-01-19
AnnouncementXML	Submission_2022-01-19_03:32:09.482.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nina Bach
SpeciesList	scientific name: Staphylococcus aureus subsp. aureus NCTC 8325; NCBI TaxID: 93061;
ModificationList	monohydroxylated residue; dimethylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion ETD

Revision	Datetime	Status	ChangeLog Entry
0	2017-10-30 02:29:54	ID requested
⏵ 1	2022-01-19 03:32:10	announced

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: Drug repurposing

antibacterial screening

bactericidal activity

SpsB

Staphylococcus aureus

MRSA

biofilm

persister

secretome

affinity-based protein profiling

chemical proteomics

photocrosslinker

Stephan A. Sieber
contact affiliation	Technische Universität München Department of Chemistry Lehrstuhl Organische Chemie II Lichtenbergstr. 4 85747 Garching (bei München)
contact email	stephan.sieber@tum.de
lab head
Nina Bach
contact affiliation	TU München
contact email	nina.bach@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/2022/01/PXD008070

PRIDE project URI

• PRIDE
  1. PXD008070
     1. Label: PRIDE project
     2. Name: Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms