The development of selective inhibitors of NagZ : increased susceptibility of Gram-negative bacteria to β-lactams
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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.
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 . DOI: 10.1002/cbic.201300395
© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This work was supported by a Wellcome Trust Fellowship to T Gloster.
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