Inhibitors of bacterial N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity

Danuta Gillner; Nicola Armoush; Richard C Holz; Daniel P Becker

doi:10.1016/j.bmcl.2009.09.077

Inhibitors of bacterial N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity

Bioorg Med Chem Lett. 2009 Nov 15;19(22):6350-2. doi: 10.1016/j.bmcl.2009.09.077. Epub 2009 Sep 24.

Authors

Danuta Gillner¹, Nicola Armoush, Richard C Holz, Daniel P Becker

Affiliation

¹ Department of Chemistry, Loyola University, 6525 North Sheridan Road, Chicago, IL 60626, USA.

PMID: 19822427
DOI: 10.1016/j.bmcl.2009.09.077

Abstract

The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a critical bacterial enzyme for the construction of the bacterial cell wall. A screen biased toward compounds containing zinc-binding groups (ZBG's) including thiols, carboxylic acids, boronic acids, phosphonates and hydroxamates has delivered a number of micromolar inhibitors of DapE from Haemophilus influenzae, including the low micromolar inhibitor L-captopril (IC(50)=3.3 microM, K(i)=1.8 microM). In vitro antimicrobial activity was demonstrated for L-captopril against Escherichia coli.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / metabolism
Amino Acid Sequence
Anti-Bacterial Agents / pharmacology*
Binding Sites
Diaminopimelic Acid / metabolism*
Enzyme Inhibitors / pharmacology*
Escherichia coli / drug effects*
Escherichia coli / enzymology
Haemophilus influenzae / drug effects*
Haemophilus influenzae / enzymology
Microbial Sensitivity Tests
Mutagenesis, Site-Directed
Substrate Specificity

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Diaminopimelic Acid
Amidohydrolases