PXD057335

PXD057335 is an original dataset announced via ProteomeXchange.

Title	ClpC1-targeting peptide natural products differentially dysregulate the proteome of Mycobacterium tuberculosis
Description	Targeting the protein quality control system in Mycobacterium tuberculosis offers a powerful and largely untapped opportunity for antibiotic development. The ClpC1:ClpP1P2 protease is an essential component of the system and is involved in both regulatory and stress-related protein degradation. Several non-ribosomal peptide natural product families have been discovered, including ecumicin, ilamycins (rufomycins) and cyclomarins, which bind to the ClpC1 chaperone and possess potent antimycobacterial activity. This has led to significant interest in these molecules, and the ClpC1:ClpP1P2 system more generally, as a bona fide target for the development of new tuberculosis drugs. In this study, we apply a systematic and multi-layered approach combining quantitative proteomics, bioinformatics, transcriptomics, CRISPRi gene knockdown, and targeted biochemical and biophysical assays to dissect the mechanisms of ecumicin, ilamycin and cyclomarin in clinically relevant Mycobacterium tuberculosis. Strikingly, despite exhibiting similar binding modes to ClpC1, each natural product elicits distinct substrate-specific effects on protein degradation. We further show that derivatives of ilamycin and ecumicin engage the stress-response chaperones ClpC2 and Hsp20 respectively with varied affinities. The differential disruption of ClpC1 substrates and stress-response chaperones, and distinct reshaping of the Mycobacterium tuberculosis proteome by the three natural products, unveils opportunities for the development of protein quality control-targeted antimycobacterials.
HostingRepository	PRIDE
AnnounceDate	2025-12-14
AnnouncementXML	Submission_2025-12-14_01:05:32.571.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mark Larance
SpeciesList	scientific name: Mycobacterium tuberculosis H37Rv; NCBI TaxID: NEWT:83332;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-29 21:44:59	ID requested
⏵ 1	2025-12-14 01:05:33	announced

Dataset with its publication pending

submitter keyword: None

Mark Larance
contact affiliation	Charles Perkins Centre, School of Medical Sciences, University of Sydney, Sydney, Australia.
contact email	mark.larance@sydney.edu.au
lab head
Mark Larance
contact affiliation	The University of Sydney
contact email	mark.larance@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057335
     1. Label: PRIDE project
     2. Name: ClpC1-targeting peptide natural products differentially dysregulate the proteome of Mycobacterium tuberculosis