1012331-05-3Relevant articles and documents
The development of selective inhibitors of nagz: Increased susceptibility of gram-negative bacteria to β-lactams
Stubbs, Keith A.,Bacik, John-Paul,Perley-Robertson, G. Evan,Whitworth, Garrett E.,Gloster, Tracey M.,Vocadlo, David J.,Mark, Brian L.
, p. 1973 - 1981 (2013)
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. The development of selective and potent inhibitors of the β-glucosaminidase NagZ, which is an important enzyme in AmpC β-lactamase expression, based on the inhibitor 2-acetamido-2-deoxynojirimycin is described. In addition, the structure of a NagZ-inhibitor complex provides insight into the molecular basis for inhibition by these compounds.
