The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to [beta]-Lactams

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. [PUBLICATION ABSTRACT]