2Q9M

4-Substituted Trinems as Broad Spectrum-Lactamase Inhibitors: Structure-based Design, Synthesis and Biological Activity

Summary for 2Q9M

• Entry DOI: 10.2210/pdb2q9m/pdb
• Related: 1XX2
• Descriptor: Beta-lactamase, (1R,4S,7AS)-1-(1-FORMYLPROP-1-EN-1-YL)-4-METHOXY-2,4,5,6,7,7A-HEXAHYDRO-1H-ISOINDOLE-3-CARBOXYLIC ACID (3 entities in total)
• Functional Keywords: beta-lactamase inhibitor, tricyclic carbapenem, hydrolase
• Biological source: Enterobacter cloacae
• Cellular location: Periplasm (By similarity): P05364
• Total number of polymer chains: 1
• Total formula weight: 39305.83

Authors

Plantan, I.,Selic, L.,Mesar, T.,Stefanic Anderluh, P.,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. (deposition date: 2007-06-13, release date: 2007-08-21, Last modification date: 2024-11-20)

Primary citation

Plantan, I.,Selic, L.,Mesar, T.,Anderluh, P.S.,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.
4-Substituted Trinems as Broad Spectrum beta-Lactamase Inhibitors: Structure-Based Design, Synthesis, and Biological Activity
J.Med.Chem., 50:4113-4121, 2007

PubMed Abstract: 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.

PubMed: 17665896
DOI: 10.1021/jm0703237

Experimental method

X-RAY DIFFRACTION (2.05 Å)