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Bicyclic enol cyclocarbamates inhibit penicillin-binding proteins
Paul Dockerty1, Jerre G Edens1, Menno B Tol2
1Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands. m.d.witte@rug.nl.
Organic & Biomolecular Chemistry
|January 4, 2017
Summary
Researchers synthesized novel enol cyclocarbamate compounds inspired by natural products. These compounds show antibacterial activity by inhibiting peptidoglycan synthesis and specific penicillin-binding proteins in bacteria.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Natural products offer promising scaffolds for developing new chemical probes and drugs.
- The antibacterial lipopeptide Brabantamide A features a unique enol cyclocarbamate structure.
Purpose of the Study:
- To synthesize a diverse library of enol cyclocarbamate derivatives.
- To identify key structural elements responsible for antibacterial efficacy.
- To elucidate the mechanism of action of these novel compounds.
Main Methods:
- Chemical synthesis of enol cyclocarbamate analogs.
- Assessment of antibacterial activity against relevant pathogens.
- Investigation of inhibition of peptidoglycan biosynthesis.
- Activity-based protein profiling to identify target enzymes.
Main Results:
- A series of enol cyclocarbamate compounds were successfully synthesized.
- Specific structural modifications enhanced antibacterial potency.
- The compounds were found to impede the incorporation of hydroxycoumarin carboxylic acid-amino d-alanine into peptidoglycan.
- Inhibition of a subset of penicillin-binding proteins (PBPs) in *B. subtilis* and *S. pneumoniae* was confirmed.
Conclusions:
- The enol cyclocarbamate scaffold is a valuable platform for developing new antibacterial agents.
- Understanding the structure-activity relationships is crucial for optimizing antibacterial properties.
- The identified mechanism involves the disruption of bacterial cell wall synthesis via PBP inhibition.
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