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J Am Chem Soc. 2013 Dec 11;135(49):18358-69. doi: 10.1021/ja403598g. Epub 2013 Dec 3.

β-Lactamase inhibition by 7-alkylidenecephalosporin sulfones: allylic transposition and formation of an unprecedented stabilized acyl-enzyme.

Author information

1
Department of Biochemistry, Case Western Reserve University , 10900 Euclid Ave., Cleveland, Ohio 44106, United States.

Abstract

The inhibition of the class A SHV-1 β-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 Å X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A cephalosporin-derived enzyme complex of this type is unprecedented, and the rearrangement leading to its formation may offer new possibilities for inhibitor design. The observed acyl-enzyme derives its stability from the resonance stabilization conveyed by the β-aminoacrylate (i.e., vinylogous urethane) functionality as there is relatively little interaction of the eight-membered ring with active site residues. Two mechanistic schemes are proposed, differing in whether, subsequent to acylation of the active site serine and opening of the β-lactam, the resultant dihydrothiazine fragments on its own or is assisted by an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7 tert-butyloxycarbonyl group. This compound was also found to be a submicromolar inhibitor of the class C ADC-7 and PDC-3 β-lactamases.

PMID:
24219313
PMCID:
PMC4042847
DOI:
10.1021/ja403598g
[Indexed for MEDLINE]
Free PMC Article

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