PXD026213

PXD026213 is an original dataset announced via ProteomeXchange.

Title	A competitive activity-based protein profiling platform yields cell wall synthesis inhibitors active against replicating and non-replicating Mycobacterium tuberculosis
Description	The identification and validation of a small molecule's targets is a major bottleneck in the discovery process for tuberculosis antibiotics. Activity-based protein profiling (ABPP) is an efficient tool for determining a small molecul's targets within complex proteomes. However, how target inhibition relates to biological activity is often left unexplored. Here we studied the effects of 1,2,3-triazole ureas on Mycobacterium tuberculosis . After screening ~200 compounds, we focused on two inhibitors active against both exponentially replicating and hypoxia-induced drug-tolerant Mtb that form part of a four-compound structure-activity series. The compound with negligible activity revealed potential false positive targets not addressed in other ABPP studies. Biochemistry, computational docking, and morphological analysis confirmed that active compounds preferentially inhibit serine hydrolases with cell wall and lipid metabolism functions and that disruption of the cell wall underlies biological activity. Our findings showed that ABPP identifies the targets most likely relevant to a compound's antibacterial activity.
HostingRepository	PRIDE
AnnounceDate	2022-06-09
AnnouncementXML	Submission_2022-06-09_04:41:36.099.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Armand Cognetta
SpeciesList	scientific name: Mycobacterium tuberculosis H37Rv; NCBI TaxID: 83332;
ModificationList	iodoacetamide derivatized residue
Instrument	LTQ; LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2021-05-24 03:46:39	ID requested
⏵ 1	2022-06-09 04:41:37	announced

Li M, Patel HV, Cognetta AB, Smith TC, Mallick I, Cavalier JF, Previti ML, Canaan S, Aldridge BB, Cravatt BF, Seeliger JC, Identification of cell wall synthesis inhibitors active against Mycobacterium tuberculosis by competitive activity-based protein profiling. Cell Chem Biol, 29(5):883-896.e5(2022) [pubmed]

submitter keyword: mycobacterium tuberculosis, abpp, drug discovery

Benjamin F. Cravatt
contact affiliation	Department of Chemistry, Scripps Research Institute
contact email	cravatt@scripps.edu
lab head
Armand Cognetta
contact affiliation	Scripps Research, Weatherwax Biotechnologies
contact email	nettacog@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026213
     1. Label: PRIDE project
     2. Name: A competitive activity-based protein profiling platform yields cell wall synthesis inhibitors active against replicating and non-replicating Mycobacterium tuberculosis