PXD007699

PXD007699 is an original dataset announced via ProteomeXchange.

Title	An antibacterial β-lactone kills Mycobacterium tuberculosis by infiltrating mycolic acid biosynthesis
Description	The spread of antibiotic resistance is a major challenge for treatment of Mycobacterium tuberculosis infection. In addition, efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis leading to rapid cell death. Inspired by this mechanism we exploit β-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β-lactones we found one hit with potent anti-mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation via enzyme assays and customized 13C metabolite profiling showed that both targets are functionally impaired by the β-lactone. Co-administration with front-line antibiotics enhanced the potency against M. tuberculosis by more than 100-fold demonstrating a therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases.
HostingRepository	PRIDE
AnnounceDate	2022-05-30
AnnouncementXML	Submission_2022-05-30_07:20:20.328.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nina Bach
SpeciesList	scientific name: Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155); NCBI TaxID: 246196; scientific name: Mycobacterium tuberculosis H37Rv; NCBI TaxID: 83332;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap XL

Revision	Datetime	Status	ChangeLog Entry
0	2017-09-08 05:56:04	ID requested
⏵ 1	2022-05-30 07:20:21	announced

Lehmann J, Cheng TY, Aggarwal A, Park AS, Zeiler E, Raju RM, Akopian T, Kandror O, Sacchettini JC, Moody DB, Rubin EJ, Sieber SA, -Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis. Angew Chem Int Ed Engl, 57(1):348-353(2018) [pubmed]

curator keyword: Biomedical

submitter keyword: Mycobacterium tuberculosis, activity-based protein profiling, lipidomics, antibiotics

Prof. Stephan A. Sieber
contact affiliation	TU München Institut für Chemie Organische Chemie II Lichtenbergstr. 4 85747 Garching
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/PXD007699

PRIDE project URI

• PRIDE
  1. PXD007699
     1. Label: PRIDE project
     2. Name: An antibacterial β-lactone kills Mycobacterium tuberculosis by infiltrating mycolic acid biosynthesis