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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jan 27

PMID 38279338

Authors

Thahani S Habeeb Mohammad

Emma H Kelley

Cory T Reidl

Katherine Konczak

Megan Beulke

Janielle Javier

Kenneth W Olsen

Daniel P Becker

Affiliations

Soon will be listed here.

Abstract

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).

Citing Articles

Synthesis of Pyrazole-Based Inhibitors of the Bacterial Enzyme -Succinyl-l,l-2,6-Diaminopimelic Acid Desuccinylase (DapE) as Potential Antibiotics.

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