PXD050993

PXD050993 is an original dataset announced via ProteomeXchange.

Title	Tailored phenyl ureas eradicate drug-resistant Mycobacterium tuberculosis by targeting mycolic acid cell wall assembly
Description	Treatment of Mycobacterium tuberculosis infections is a challenging task due to a growing number of resistant clinical isolates as well as an almost empty drug development pipeline. To identify new antibiotic hits, we screened a focused library of 400 synthetic compounds derived from a recently discovered molecule with promising anti-mycobacterial activity. A suite of more potent hit molecules was deciphered with sub-micromolar activity. Utilising tailored affinity-based probes for chemical proteomic investigations, we successfully pinpointed the mycolic acid transporter MmpL3 and two epoxide hydrolases, EphD and EphF, also linked to mycolic acid biosynthesis, as specific targets of the compounds. These targets were thoroughly and independently validated by activity assays, under- and overexpression, resistance generation, and proteomic studies. Structural refinement of the most potent hit molecules led to the development of a new lead compound that demonstrates enhanced biological activity in M. tuberculosis, low human cytotoxicity, and improved solubility and oral bioavailability − traits that are often challenging to achieve with anti-mycobacterial drugs. Overall, drug-likeness, as well as the dual mode of action, addressing the mycolic acid cell wall assembly at two distinct steps, holds significant potential for further in vivo applications.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_15:48:42.668.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dietrich Mostert
SpeciesList	scientific name: Mycobacterium tuberculosis H37Ra; NCBI TaxID: 419947;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF; timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-26 10:13:33	ID requested
⏵ 1	2025-05-06 15:48:43	announced

Mostert D, Braun J, Zimmerman MD, Engelhart CA, Berndl S, Quoika PK, Kany AM, Proietto J, Penalva-Lopez S, Wallach JB, Hirsch AKH, Zacharias M, Schnappinger D, Dartois V, Sieber SA, by targeting mycolic acid cell wall assembly. Chem Sci, 16(21):9472-9483(2025) [pubmed]

10.1039/d5sc02565f;

submitter keyword: Tuberculosis, AfBPP

Stephan A. Sieber
contact affiliation	TUM Center for Functional Protein Assemblies (CPA), Department of Chemistry and Chair of Organic Chemistry II, Technical University of Munich, Lichtenbergstraße 4, 85748 Garching, Germany.
contact email	stephan.sieber@tum.de
lab head
Dietrich Mostert
contact affiliation	Center for Functional Protein Assemblies (CPA), Department of Chemistry, Chair of Organic Chemistry II, Technical University of Munich, 85748 Garching, Germany.
contact email	dietrich.mostert@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/2025/05/PXD050993

PRIDE project URI

• PRIDE
  1. PXD050993
     1. Label: PRIDE project
     2. Name: Tailored phenyl ureas eradicate drug-resistant Mycobacterium tuberculosis by targeting mycolic acid cell wall assembly