Projects per year
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.
Original language | English |
---|---|
Pages (from-to) | 1973-1981 |
Journal | ChemBioChem |
Volume | 14 |
Issue number | 15 |
Early online date | 5 Sept 2013 |
DOIs | |
Publication status | Published - Oct 2013 |
Keywords
- Carbohydrates
- Inhibitors
- Enzymes
- Selectivity
- Synthesis
Fingerprint
Dive into the research topics of 'The development of selective inhibitors of NagZ: increased susceptibility of Gram-negative bacteria to β-lactams'. Together they form a unique fingerprint.Projects
- 1 Finished
-
Tracey Gloster Fellowship: Understanding degradation of heparan sulphate with implications for disease
Gloster, T. (PI)
1/01/12 → 30/09/18
Project: Fellowship