尾-Lactamase Inhibition by 7-Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of an Unprecedented Stabilized Acyl-Enzyme

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• 作者：Elizabeth A. Rodkey ; David C. McLeod ; Christopher R. Bethel ; Kerri M. Smith ; Yan Xu ; Weirui Chai ; Tao Che ; Paul R. Carey ; Robert A. Bonomo ; Focco van den Akker ; John D. Buynak
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：December 11, 2013
• 年：2013
• 卷：135
• 期：49
• 页码：18358-18369
• 全文大小：728K
• 年卷期：v.135,no.49(December 11, 2013)
• ISSN：1520-5126

文摘

The inhibition of the class A SHV-1 尾-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 脜 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 尾-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 尾-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 尾-lactamases.