Centre d'Ingénierie des Protéines and Centre de Recherches du Cyclotron, Université de Liège, B-4000 Sart Tilman, Belgium.
J Am Chem Soc. 2009 Oct 28;131(42):15262-9. doi: 10.1021/ja9051526.
6-Beta-halogenopenicillanates are powerful, irreversible inhibitors of various beta-lactamases and penicillin-binding proteins. Upon acylation of these enzymes, the inhibitors are thought to undergo a structural rearrangement associated with the departure of the iodide and formation of a dihydrothiazine ring, but, to date, no structural evidence has proven this. 6-Beta-iodopenicillanic acid (BIP) is shown here to be an active antibiotic against various bacterial strains and an effective inhibitor of the class A beta-lactamase of Bacillus subtilis BS3 (BS3) and the D,D-peptidase of Actinomadura R39 (R39). Crystals of BS3 and of R39 were soaked with a solution of BIP and their structures solved at 1.65 and 2.2 A, respectively. The beta-lactam and the thiazolidine rings of BIP are indeed found to be fused into a dihydrothiazine ring that can adopt two stable conformations at these active sites. The rearranged BIP is observed in one conformation in the BS3 active site and in two monomers of the asymmetric unit of R39, and is observed in the other conformation in the other two monomers of the asymmetric unit of R39. The BS3 structure reveals a new mode of carboxylate interaction with a class A beta-lactamase active site that should be of interest in future inhibitor design.
6-β-卤代青霉烷酸盐是各种β-内酰胺酶和青霉素结合蛋白的强、不可逆抑制剂。这些酶被酰化后，抑制剂被认为会发生结构重排，伴随着碘化物的离去和二氢噻嗪环的形成，但迄今为止，还没有结构证据证明这一点。这里显示 6-β-碘代青霉烷酸（BIP）是一种对抗各种细菌株具有活性的抗生素，也是枯草芽孢杆菌 BS3（BS3）的 A 类β-内酰胺酶和 Actinomadura R39（R39）的 D，D-肽酶的有效抑制剂。BS3 和 R39 的晶体分别用 BIP 的溶液浸泡，并分别在 1.65 和 2.2 A 的分辨率下解决其结构。BIP 的β-内酰胺和噻唑烷环确实融合成一个二氢噻嗪环，在这些活性部位可以采用两种稳定的构象。在 BS3 的活性部位的一个构象中观察到重排的 BIP，在 R39 的不对称单元的两个单体中观察到另一个构象，在 R39 的不对称单元的另外两个单体中观察到另一个构象。BS3 的结构揭示了一种新的羧酸盐与 A 类β-内酰胺酶活性部位相互作用的模式，这在未来的抑制剂设计中应该是有趣的。
