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

ABSTRACT: The increasing incidence of inducible chromosomal AmpC ?-lactamases within the clinic is a growing concern because these enzymes deactivate a broad range of even the most recently developed ?-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 ?-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 ?-lactams against a clinically relevant Gram-negative bacterium bearing inducible chromosomal AmpC ?-lactamase, Pseudomonas aeruginosa. The structure of a NagZ-inhibitor complex provides insight into the molecular basis for inhibition by these compounds.

SUBMITTER: Stubbs KA 

PROVIDER: S-EPMC3920638 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature