The development of selective inhibitors of NagZ: increased susceptibility of Gram-negative bacteria to β-lactams

K.A. Stubbs, J.-P. Bacik, G.E. Perley-Robertson, G.E. Whitworth, T.M. Gloster, D.J. Vocadlo, B.L. Mark

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25 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)1973-1981
JournalChemBioChem
Volume14
Issue number15
Early online date5 Sept 2013
DOIs
Publication statusPublished - Oct 2013

Keywords

  • Carbohydrates
  • Inhibitors
  • Enzymes
  • Selectivity
  • Synthesis

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