The development of selective inhibitors of NagZ : increased susceptibility of Gram-negative bacteria to β-lactams
Abstract
The increasing incidence of inducible chromosomal AmpC β-lactamases within the clinic is a growing concern because these enzymes deactivate a broad range of even the most recently developed β-lactam antibiotics. As a result, new strategies are needed to block the action of this antibiotic resistance enzyme. Presented here is a strategy to combat the action of inducible AmpC by inhibiting the β-glucosaminidase NagZ, which is an enzyme involved in regulating the induction of AmpC expression. A divergent route facilitating the rapid synthesis of a series of N-acyl analogues of 2-acetamido-2-deoxynojirimycin is reported here. Among these compounds are potent NagZ inhibitors that are selective against functionally related human enzymes. These compounds reduce minimum inhibitory concentration values for β-lactams against a clinically relevant Gram-negative bacterium bearing inducible chromosomal AmpC β-lactamase, Pseudomonas aeruginosa. The structure of a NagZ-inhibitor complex provides insight into the molecular basis for inhibition by these compounds.
Citation
Stubbs , K A , Bacik , J-P , Perley-Robertson , G E , Whitworth , G E , Gloster , T M , Vocadlo , D J & Mark , B L 2013 , ' The development of selective inhibitors of NagZ : increased susceptibility of Gram-negative bacteria to β-lactams ' , ChemBioChem , vol. 14 , no. 15 , pp. 1973-1981 . https://doi.org/10.1002/cbic.201300395
Publication
ChemBioChem
Status
Peer reviewed
ISSN
1439-4227Type
Journal article
Description
This work was supported by a Wellcome Trust Fellowship to T Gloster.Collections
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