The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams

摘要: The increasing incidence of inducible chromosomal AmpC β-lactamases within the clinic is a growing concern because these enzymes deactivate broad range even most recently developed β-lactam antibiotics. As result, new strategies are needed to block action this antibiotic resistance enzyme. Presented here strategy combat by inhibiting β-glucosaminidase NagZ, which an enzyme involved in regulating induction expression. A divergent route facilitating rapid synthesis series N-acyl analogues 2-acetamido-2-deoxynojirimycin reported here. Among compounds potent NagZ inhibitors that selective against functionally related human enzymes. These reduce minimum inhibitory concentration values for β-lactams clinically relevant Gram-negative bacterium bearing β-lactamase, Pseudomonas aeruginosa. structure NagZ–inhibitor complex provides insight into molecular basis inhibition compounds.