title: The development of selective inhibitors of NagZ: increased susceptibility of Gram-negative bacteria to β-lactams.
abstract: 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.
authors.affiliation: School of Chemistry and Biochemistry, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009 (Australia). keith.stubbs@uwa.edu.au.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Stubbs
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Bacik
authors.forename: G Evan
authors.initials: GE
authors.lastname: Perley-Robertson
authors.forename: Garrett E
authors.initials: GE
authors.lastname: Whitworth
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Gloster
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
authors.forename: Brian L
authors.initials: BL
authors.lastname: Mark
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology*; D006596:Hexosaminidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010457:Peptidoglycan / Q000378:metabolism; D011487:Protein Conformation; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D047090:beta-Lactams; D006596:Hexosaminidases
keywords: carbohydrates; enzymes; inhibitors; selectivity; synthesis