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The development of selective inhibitors of NagZ : increased susceptibility of Gram-negative bacteria to β-lactams
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dc.contributor.author | Stubbs, K.A. | |
dc.contributor.author | Bacik, J.-P. | |
dc.contributor.author | Perley-Robertson, G.E. | |
dc.contributor.author | Whitworth, G.E. | |
dc.contributor.author | Gloster, T.M. | |
dc.contributor.author | Vocadlo, D.J. | |
dc.contributor.author | Mark, B.L. | |
dc.date.accessioned | 2013-09-18T15:31:01Z | |
dc.date.available | 2013-09-18T15:31:01Z | |
dc.date.issued | 2013-10 | |
dc.identifier | 70322859 | |
dc.identifier | 2be8736e-c43c-4b40-acc2-1e0d74bbe696 | |
dc.identifier | 84885429563 | |
dc.identifier.citation | Stubbs , K A , Bacik , J-P , Perley-Robertson , G E , Whitworth , G E , Gloster , T M , Vocadlo , D J & Mark , B L 2013 , ' The development of selective inhibitors of NagZ : increased susceptibility of Gram-negative bacteria to β-lactams ' , ChemBioChem , vol. 14 , no. 15 , pp. 1973-1981 . https://doi.org/10.1002/cbic.201300395 | en |
dc.identifier.issn | 1439-4227 | |
dc.identifier.uri | https://hdl.handle.net/10023/4060 | |
dc.description | This work was supported by a Wellcome Trust Fellowship to T Gloster. | en |
dc.description.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. | |
dc.format.extent | 743348 | |
dc.language.iso | eng | |
dc.relation.ispartof | ChemBioChem | en |
dc.subject | Carbohydrates | en |
dc.subject | Inhibitors | en |
dc.subject | Enzymes | en |
dc.subject | Selectivity | en |
dc.subject | Synthesis | en |
dc.subject | QD Chemistry | en |
dc.subject.lcc | QD | en |
dc.title | The development of selective inhibitors of NagZ : increased susceptibility of Gram-negative bacteria to β-lactams | en |
dc.type | Journal article | en |
dc.contributor.sponsor | The Wellcome Trust | en |
dc.contributor.institution | University of St Andrews. School of Biology | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.identifier.doi | 10.1002/cbic.201300395 | |
dc.description.status | Peer reviewed | en |
dc.identifier.grantnumber | 095828/Z/11/Z | en |
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