PXD050437 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-03-07 00:56:50 | ID requested | |
⏵ 1 | 2024-06-26 07:39:41 | announced | |
Publication List
Keyword List
submitter keyword: antibiotics, SAR, MoA studies, target identification,Isocyanide, covalent inhibitors |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD050437
- Label: PRIDE project
- Name: Isocyanides inhibit bacterial pathogents by covalent targeting of essential metabolic enzymes