Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases.
J Enzyme Inhib Med Chem
; 34(1): 1010-1017, 2019 Dec.
Article
em En
| MEDLINE
| ID: mdl-31072165
ABSTRACT
The Mur ligases form a series of consecutive enzymes that participate in the intracellular steps of bacterial peptidoglycan biosynthesis. They therefore represent interesting targets for antibacterial drug discovery. MurC, D, E and F are all ATP-dependent ligases. Accordingly, with the aim being to find multiple inhibitors of these enzymes, we screened a collection of ATP-competitive kinase inhibitors, on Escherichia coli MurC, D and F, and identified five promising scaffolds that inhibited at least two of these ligases. Compounds 1, 2, 4 and 5 are multiple inhibitors of the whole MurC to MurF cascade that act in the micromolar range (IC50, 32-368 µM). NMR-assisted binding studies and steady-state kinetics studies performed on aza-stilbene derivative 1 showed, surprisingly, that it acts as a competitive inhibitor of MurD activity towards D-glutamic acid, and additionally, that its binding to the D-glutamic acid binding site is independent of the enzyme closure promoted by ATP.
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Base de dados:
MEDLINE
Assunto principal:
Trifosfato de Adenosina
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Inibidores Enzimáticos
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Escherichia coli
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Ligases
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Antibacterianos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article