Cyclobutanone Inhibitors of Diaminopimelate Desuccinylase (DapE) as Potential New Antibiotics

Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibio...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-01, Vol.25 (2), p.1339
Main Authors: Habeeb Mohammad, Thahani S, Kelley, Emma H, Reidl, Cory T, Konczak, Katherine, Beulke, Megan, Javier, Janielle, Olsen, Kenneth W, Becker, Daniel P
Format: Article
Language:English
Subjects:
Amino acids
Anti-Bacterial Agents - pharmacology
antibiotic
Antibiotics
Bacteria
Bacterial infections
Binding sites
cyclobutanone
DapE
diaminopimelate desuccinylase
Drug dosages
Drug therapy
enzyme inhibitor
Enzyme Inhibitors - pharmacology
Enzymes
Gram-positive bacteria
Ligands
Molecular Docking Simulation
peptidomimetic
Small libraries
Citations: Items that this one cites
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Summary:Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor ( , IC = 23.1 µM) enabled determination of a K value of 10.2 +/- 0.26 µM and observed two separate T values for DapE ( DapE).
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25021339