PUBLICATION
Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex
- Authors
- Paulussen, F.M., Schouten, G.K., Moertl, C., Verheul, J., Hoekstra, I., Koningstein, G.M., Hutchins, G.H., Alkir, A., Luirink, R.A., Geerke, D.P., van Ulsen, P., den Blaauwen, T., Luirink, J., Grossmann, T.N.
- ID
- ZDB-PUB-220811-1
- Date
- 2022
- Source
- Journal of the American Chemical Society 144(33): 15303-15313 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/metabolism
- Anti-Bacterial Agents/pharmacology
- Bacterial Proteins/metabolism
- Cell Cycle Proteins/chemistry
- Escherichia coli/metabolism
- Escherichia coli Proteins*/chemistry
- Membrane Proteins/chemistry
- Zebrafish/metabolism
- PubMed
- 35945166 Full text @ J. Am. Chem. Soc.
Citation
Paulussen, F.M., Schouten, G.K., Moertl, C., Verheul, J., Hoekstra, I., Koningstein, G.M., Hutchins, G.H., Alkir, A., Luirink, R.A., Geerke, D.P., van Ulsen, P., den Blaauwen, T., Luirink, J., Grossmann, T.N. (2022) Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex. Journal of the American Chemical Society. 144(33):15303-15313.
Abstract
The use of antibiotics is threatened by the emergence and spread of multidrug-resistant strains of bacteria. Thus, there is a need to develop antibiotics that address new targets. In this respect, the bacterial divisome, a multi-protein complex central to cell division, represents a potentially attractive target. Of particular interest is the FtsQB subcomplex that plays a decisive role in divisome assembly and peptidoglycan biogenesis in E. coli. Here, we report the structure-based design of a macrocyclic covalent inhibitor derived from a periplasmic region of FtsB that mediates its binding to FtsQ. The bioactive conformation of this motif was stabilized by a customized cross-link resulting in a tertiary structure mimetic with increased affinity for FtsQ. To increase activity, a covalent handle was incorporated, providing an inhibitor that impedes the interaction between FtsQ and FtsB irreversibly. The covalent inhibitor reduced the growth of an outer membrane-permeable E. coli strain, concurrent with the expected loss of FtsB localization, and also affected the infection of zebrafish larvae by a clinical E. coli strain. This first-in-class inhibitor of a divisome protein-protein interaction highlights the potential of proteomimetic molecules as inhibitors of challenging targets. In particular, the covalent mode-of-action can serve as an inspiration for future antibiotics that target protein-protein interactions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping