The development of selective inhibitors of NagZ: increased susceptibility of Gram-negative bacteria to beta-lactams.
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Stubbs KA, Bacik JP, Perley-Robertson GE, Whitworth GE, Gloster TM, Vocadlo DJ, Mark BL
The development of selective inhibitors of NagZ: increased susceptibility of Gram-negative bacteria to beta-lactams.
Chembiochem. 2013 Oct 11;14(15):1973-81. doi: 10.1002/cbic.201300395. Epub 2013 Sep 5.
- PubMed ID
- 24009110 [ View in PubMed]
- Abstract
The increasing incidence of inducible chromosomal AmpC beta-lactamases within the clinic is a growing concern because these enzymes deactivate a broad range of even the most recently developed beta-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 beta-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 beta-lactams against a clinically relevant Gram-negative bacterium bearing inducible chromosomal AmpC beta-lactamase, Pseudomonas aeruginosa. The structure of a NagZ-inhibitor complex provides insight into the molecular basis for inhibition by these compounds.