Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Chem Commun (Camb). 2020 Mar 10;56(20):3047-3049. doi: 10.1039/d0cc00356e.
A series of aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) were chemoenzymatically synthesized via the addition of various mono- and diamine substrates to fumaric acid catalyzed by the enzyme EDDS lyase. Many of these novel AMA and EDDS analogues demonstrate potent inhibition of the bacterial metallo-β-lactamase NDM-1. Isothermal titration calorimetry assays revealed a strong correlation between the inhibitory potency of the compounds and their ability to bind zinc. Compounds 1a (AMA), 1b (AMB), 5 (EDDS), followed by 1d and 8a, demonstrate the highest synergy with meropenem resensitizing an NDM-1 producing strain of E. coli to this important carbapenem of last resort.
一系列 Aspergillomarasmine A（AMA）和乙二胺-N,N'-二琥珀酸（EDDS）的氨基羧酸类似物通过酶 EDDS 裂合酶催化的各种单胺和二胺底物与富马酸的加成反应化学酶法合成。这些新型 AMA 和 EDDS 类似物中的许多都表现出对细菌金属β-内酰胺酶 NDM-1 的强烈抑制作用。等温滴定量热法测定表明，化合物的抑制效力与其结合锌的能力之间存在很强的相关性。化合物 1a（AMA）、1b（AMB）、5（EDDS），其次是 1d 和 8a，与美罗培南表现出最高的协同作用，使产 NDM-1 的大肠杆菌对这种重要的最后手段碳青霉烯类药物重新敏感。
