2q9n
From Proteopedia
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==Overview== | ==Overview== | ||
| - | A wide variety of pathogens have acquired antimicrobial resistance as an | + | A wide variety of pathogens have acquired antimicrobial resistance as an inevitable evolutionary response to the extensive use of antibacterial agents. In particular, one of the most widely used antibiotic structural classes is the beta-lactams, in which the most common and the most efficient mechanism of bacterial resistance is the synthesis of beta-lactamases. Class C beta-lactamase enzymes are primarily cephalosporinases, mostly chromosomally encoded, and are inducible by exposure to some beta-lactam agents and resistant to inhibition by marketed beta-lactamase inhibitors. In an ongoing effort to alleviate this problem a series of novel 4-substituted trinems was designed and synthesized. Significant in vitro inhibitory activity was measured against the bacterial beta-lactamases of class C and additionally against class A. The lead compound LK-157 was shown to be a potent mechanism-based inactivator. Acylation of the active site Ser 64 of the class C enzyme beta-lactamase was observed in the solved crystal structures of two inhibitors complexes to AmpC enzyme from E. cloacae. Structure-activity relationships in the series reveal the importance of the trinem scaffold for inhibitory activity and the interesting potential of the series for further development. |
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
| - | 4-Substituted | + | 4-Substituted trinems as broad spectrum beta-lactamase inhibitors: structure-based design, synthesis, and biological activity., Plantan I, Selic L, Mesar T, Anderluh PS, Oblak M, Prezelj A, Hesse L, Andrejasic M, Vilar M, Turk D, Kocijan A, Prevec T, Vilfan G, Kocjan D, Copar A, Urleb U, Solmajer T, J Med Chem. 2007 Aug 23;50(17):4113-21. Epub 2007 Aug 1. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17665896 17665896] |
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Enterobacter cloacae]] | [[Category: Enterobacter cloacae]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Anderluh, P | + | [[Category: Anderluh, P Stefanic.]] |
[[Category: Andrejasic, M.]] | [[Category: Andrejasic, M.]] | ||
[[Category: Copar, A.]] | [[Category: Copar, A.]] | ||
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[[Category: tricyclic carbapenem]] | [[Category: tricyclic carbapenem]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:37:34 2008'' |
Revision as of 16:37, 21 February 2008
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4-Substituted Trinems as Broad Spectrum-Lactamase Inhibitors: Structure-based Design, Synthesis and Biological Activity
Overview
A wide variety of pathogens have acquired antimicrobial resistance as an inevitable evolutionary response to the extensive use of antibacterial agents. In particular, one of the most widely used antibiotic structural classes is the beta-lactams, in which the most common and the most efficient mechanism of bacterial resistance is the synthesis of beta-lactamases. Class C beta-lactamase enzymes are primarily cephalosporinases, mostly chromosomally encoded, and are inducible by exposure to some beta-lactam agents and resistant to inhibition by marketed beta-lactamase inhibitors. In an ongoing effort to alleviate this problem a series of novel 4-substituted trinems was designed and synthesized. Significant in vitro inhibitory activity was measured against the bacterial beta-lactamases of class C and additionally against class A. The lead compound LK-157 was shown to be a potent mechanism-based inactivator. Acylation of the active site Ser 64 of the class C enzyme beta-lactamase was observed in the solved crystal structures of two inhibitors complexes to AmpC enzyme from E. cloacae. Structure-activity relationships in the series reveal the importance of the trinem scaffold for inhibitory activity and the interesting potential of the series for further development.
About this Structure
2Q9N is a Single protein structure of sequence from Enterobacter cloacae with as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
4-Substituted trinems as broad spectrum beta-lactamase inhibitors: structure-based design, synthesis, and biological activity., Plantan I, Selic L, Mesar T, Anderluh PS, Oblak M, Prezelj A, Hesse L, Andrejasic M, Vilar M, Turk D, Kocijan A, Prevec T, Vilfan G, Kocjan D, Copar A, Urleb U, Solmajer T, J Med Chem. 2007 Aug 23;50(17):4113-21. Epub 2007 Aug 1. PMID:17665896
Page seeded by OCA on Thu Feb 21 18:37:34 2008
Categories: Beta-lactamase | Enterobacter cloacae | Single protein | Anderluh, P Stefanic. | Andrejasic, M. | Copar, A. | Hesse, L. | Kocijan, A. | Kocjan, D. | Mesar, T. | Oblak, M. | Plantan, I. | Prevec, T. | Prezelj, A. | Selic, L. | Solmajer, T. | Turk, D. | Urleb, U. | Vilar, M. | Vilfan, G. | LK5 | Beta-lactamase inhibitor | Hydrolase | Tricyclic carbapenem
