PXD053165-1

PXD053165 is an original dataset announced via ProteomeXchange.

Title	Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones
Description	Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antituberculotic drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-D-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites in vivo. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement against electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized a set of various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for all antimycobacterial compounds by enzymatic inhibition assays and protein mass spectrometry analysis.
HostingRepository	PRIDE
AnnounceDate	2024-09-11
AnnouncementXML	Submission_2024-09-11_00:27:40.929.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thomas Krüger
SpeciesList	scientific name: Mycobacterium tuberculosis KT-0001; NCBI TaxID: 1400870;
ModificationList	phosphorylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-17 00:46:22	ID requested
⏵ 1	2024-09-11 00:27:41	announced

10.1016/J.EJMECH.2024.116849;

submitter keyword: LC-MS,Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones

Axel A. Brakhage
contact affiliation	Department for Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena - Leibniz-HKI, Jena Germany
contact email	axel.brakhage@leibniz-hki.de
lab head
Thomas Krüger
contact affiliation	Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute
contact email	thomas.krueger@leibniz-hki.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053165
     1. Label: PRIDE project
     2. Name: Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones