Identification of novel small molecule inhibitors of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) kinase of Gram-negative bacteria.
Identification of novel small molecule inhibitors of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) kinase of Gram-negative bacteria.
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DOI：
10.1016/j.bmc.2011.08.012
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发表时间：
2011-10-01
影响因子：
3.5
通讯作者：
Lai, K.
中科院分区：
文献类型：
--
作者：
Tang, M.;Odejinmi, S. I.;Allette, Y. M.;Vankayalapati, H.;Lai, K.
关键词：
The biosyntheses of isoprenoids is essential for the survival in all living organisms, and requires one of the two biochemical pathways: (a) Mevalonate (MVA) Pathway or (b) Methylerythritol Phosphate (MEP) Pathway. The latter pathway, which is used by all Gram-negative bacteria, some Gram-positive bacteria and a few apicomplexan protozoa, provides an attractive target for the development of new antimicrobials because of its absence in humans. In this report, we describe two different approaches that we used to identify novel small molecule inhibitors of Escherichia coli and Yersinia pestis 4-diphosphocytidyl-2-C-methyl D-erythritol (CDP-ME) kinases, key enzymes of the MEP pathway encoded by the E. coli ispE and Y. pestis ipk genes, respectively. In the first approach, we explored existing inhibitors of the GHMP kinases while in the second approach; we performed computational high-throughput screening of compound libraries by targeting the CDP-ME binding site of the two bacterial enzymes. From the first approach, we identified two compounds with 6-(benzylthio)-2-(2-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile and (Z)-3-methyl-4-((5-phenylfuran-2-yl)methylene)isoxazol-5(4H)-one scaffolds which inhibited Escherichia coli CDP-ME kinase in vitro. We then performed substructure search and docking experiments based on these two scaffolds and identified twenty three analogs for structure-activity relationship (SAR) studies. Three new compounds from the isoxazol-5(4H)-one series have shown inhibitory activities against E. coli and Y. pestis CDP-ME kinases with the IC50 values ranging from 7μM to 13μM. The second approach by computational high-throughput screening (HTS) of two million drug-like compounds yielded two compounds with benzenesulfonamide and acetamide moieties which, at a concentration of 20μM, inhibited 80% and 65%, respectively, of control CDP-ME kinase activity.
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影响因子：
5.1
作者：
Tang, M.;Wierenga, K.;Lai, K.
通讯作者：
Lai, K.
影响因子：
4.8
作者：
Fu, ZJ;Wang, M;Kim, JJP
通讯作者：
Kim, JJP
影响因子：
2.9
作者：
Krishna, SS;Zhou, T;Zhang, H
通讯作者：
Zhang, H
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3.4
作者：
Hirsch, Anna K. H.;Lauw, Susan;Diederich, Francois
通讯作者：
Diederich, Francois
影响因子：
56.9
作者：
HERZBERG, O;MOULT, J
通讯作者：
MOULT, J