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.
The molecular structure of the title tricyclic compound, C(17)H(21)NO(4), which is the immediate precursor of a potent synthetic inhibitor [Lek157: sodium (8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylate] with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclohexyl ring and the carbonyl group of the beta-lactam ring, which takes part in the formation of the initial tetrahedral acyl-enzyme complex. In this hydrophobic molecule, the overall geometry is influenced by C[bond]H...O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) A, with corresponding normalized H.O distances of 2.30 and 2.46 A], whereas the molecules are interconnected through intermolecular C[bond]H...O hydrogen bonds [3.335 (4)-3.575 (5) A].
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