PXD050437

PXD050437 is an original dataset announced via ProteomeXchange.

Title	Isocyanides inhibit bacterial pathogents by covalent targeting of essential metabolic enzymes
Description	Isonitrile (also termed isocyanide) natural products exhibit potent antimicrobial activities, but little is known about their molecular targets. Here, we focus on the so far neglected group of monoisonitriles to gain further insights into their antimicrobial mode of action (MoA). Screening a focused monoisonitrile library revealed a potent S. aureus growth inhibitor with a different MoA compared to previously described diisonitrile antibiotics. Chemical proteomics via competitive cysteine reactivity profiling, unraveled covalent modifications of two essential metabolic enzymes involved in the fatty acid biosynthetic process (FabF) and the hexosamine pathway (GlmS) at their active site cysteines. In-depth studies with the recombinant enzymes demonstrated concentration-dependent labeling, covalent binding to the catalytic site and corresponding functional inhibition by the isocyanide. Thermal proteome profiling and full proteome studies of compound-treated S. aureus further highlighted the destabilization and dysregulation of proteins related to the targeted pathways. The here described novel, covalent isocyanide MoA highlights the versatility of the functional group, making it a great tool and out-of-the-box starting point for the development of innovative antibiotics.
HostingRepository	PRIDE
AnnounceDate	2024-06-26
AnnouncementXML	Submission_2024-06-26_07:39:41.175.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nina Bach
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-07 00:56:50	ID requested
⏵ 1	2024-06-26 07:39:41	announced

10.1039/D4SC01940G;

submitter keyword: antibiotics, SAR, MoA studies, target identification,Isocyanide, covalent inhibitors

Stephan Axel Sieber
contact affiliation	Center for Functional Protein Assemblies, Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Ernst-Otto-Fischer-Straße 8, D-85748 Garching, Germany
contact email	stephan.sieber@tum.de
lab head
Nina Bach
contact affiliation	TU München
contact email	nina.bach@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050437
     1. Label: PRIDE project
     2. Name: Isocyanides inhibit bacterial pathogents by covalent targeting of essential metabolic enzymes