2-氨基-4-羟基嘧啶-5-羧酸酯的抗菌活性及其与伯克霍尔德菌 2-C-甲基-D-赤藓醇-2,4-环二磷酸合酶的结合。
Antibacterial activity of 2-amino-4-hydroxypyrimidine-5-carboxylates and binding to Burkholderia pseudomallei 2-C-methyl-d-erythritol-2,4-cyclodiphosphate synthase.
机构信息
Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA.
Department of Biological Sciences, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA.
出版信息
Bioorg Med Chem Lett. 2019 Oct 15;29(20):126660. doi: 10.1016/j.bmcl.2019.126660. Epub 2019 Sep 3.
Enzymes in the methylerythritol phosphate pathway make attractive targets for antibacterial activity due to their importance in isoprenoid biosynthesis and the absence of the pathway in mammals. The fifth enzyme in the pathway, 2-C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), contains a catalytically important zinc ion in the active site. A series of de novo designed compounds containing a zinc binding group was synthesized and evaluated for antibacterial activity and interaction with IspF from Burkholderia pseudomallei, the causative agent of Whitmore's disease. The series demonstrated antibacterial activity as well as protein stabilization in fluorescence-based thermal shift assays. Finally, the binding of one compound to Burkholderia pseudomallei IspF was evaluated through group epitope mapping by saturation transfer difference NMR.
甲基赤藓醇磷酸途径中的酶由于其在异戊烯基生物合成中的重要性以及哺乳动物中不存在该途径，成为抗菌活性的有吸引力的靶标。该途径的第五种酶，2-C-甲基-D-赤藓醇-2,4-环二磷酸合酶（IspF），在活性位点含有一个催化上重要的锌离子。合成了一系列含有锌结合基团的从头设计的化合物，并评估了它们对导致惠特莫尔病的伯克霍尔德氏菌的抗菌活性和与 IspF 的相互作用。该系列化合物表现出抗菌活性和荧光基热转移测定中的蛋白质稳定性。最后，通过饱和转移差 NMR 进行基团表位作图评估了一种化合物与伯克霍尔德氏菌 IspF 的结合。
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