The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Wiley Blackwell
2015
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| Online Access: | http://hdl.handle.net/1721.1/96858 |
| _version_ | 1826192742060916736 |
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| author | Stubbs, Keith A. Bacik, John-Paul Perley-Robertson, G. Evan Whitworth, Garrett E. Gloster, Tracey M. Vocadlo, David J. Mark, Brian L. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Stubbs, Keith A. Bacik, John-Paul Perley-Robertson, G. Evan Whitworth, Garrett E. Gloster, Tracey M. Vocadlo, David J. Mark, Brian L. |
| author_sort | Stubbs, Keith A. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:28:32Z |
| format | Article |
| id | mit-1721.1/96858 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:28:32Z |
| publishDate | 2015 |
| publisher | Wiley Blackwell |
| record_format | dspace |
| spelling | mit-1721.1/968582022-09-30T14:37:53Z The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams Stubbs, Keith A. Bacik, John-Paul Perley-Robertson, G. Evan Whitworth, Garrett E. Gloster, Tracey M. Vocadlo, David J. Mark, Brian L. Massachusetts Institute of Technology. Department of Chemistry Whitworth, Garrett E. 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. Natural Sciences and Engineering Research Council of Canada (Fellowship) 2015-04-30T14:36:55Z 2015-04-30T14:36:55Z 2013-09 2013-06 Article http://purl.org/eprint/type/JournalArticle 14394227 1439-7633 http://hdl.handle.net/1721.1/96858 Stubbs, Keith A. et al. “The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to Β-Lactams.” ChemBioChem 14.15 (2013): 1973–1981. en_US http://dx.doi.org/10.1002/cbic.201300395 ChemBioChem Creative Commons Attribution http://creativecommons.org/licenses/by/3.0/ application/pdf Wiley Blackwell Wiley Blackwell |
| spellingShingle | Stubbs, Keith A. Bacik, John-Paul Perley-Robertson, G. Evan Whitworth, Garrett E. Gloster, Tracey M. Vocadlo, David J. Mark, Brian L. The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams |
| title | The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams |
| title_full | The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams |
| title_fullStr | The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams |
| title_full_unstemmed | The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams |
| title_short | The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to β-Lactams |
| title_sort | development of selective inhibitors of nagz increased susceptibility of gram negative bacteria to β lactams |
| url | http://hdl.handle.net/1721.1/96858 |
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