Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii.
Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii.
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DOI：
10.1021/jm301709s
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发表时间：
2013-03-28
影响因子：
7.3
通讯作者：
Aldrich, Courtney C.
中科院分区：
文献类型：
--
作者：
Neres, Joao;Engelhart, Curtis A.;Drake, Eric J.;Wilson, Daniel J.;Fu, Peng;Boshoff, Helena I.;Barry, Clifton E., III;Gulick, Andrew M.;Aldrich, Courtney C.
铁载体是由细菌和其他微生物产生的小分子铁螯合剂，用于在铁限制条件下生存，例如在哺乳动物宿主中发现。铁载体的生物合成对许多重要的革兰氏阴性病原体的毒力至关重要，包括鲍曼不动杆菌、肺炎克雷伯菌、铜绿假单胞菌和大肠杆菌。我们对鲍曼假杆菌中参与铁载体生物合成的碱基进行了高通量筛选，鉴定出6-苯基-1-（吡啶-4-甲基）- 1h -pyrazolo[3,4-b]吡啶-4-羧酸15。在这里，我们报告的合成，生化和微生物评价的系统系列的类似物的HTS命中15。类似物67是最有效的类似物，对碱基的KD为2 nM。碱基抑制剂的结构表征表明，它们在活性位点以独特的方向结合，占据了所有三个底物结合位点，因此可以被认为是多底物抑制剂。这些结果为今后提高酶效和抗菌活性的研究奠定了基础。
Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions, such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening of against BasE, which is involved in siderophore biosynthesis in A. baumannii and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a KD of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveal they bind in a unique orientation in the active site occupying all three substrate binding sites, and thus can be considered multisubstrate inhibitors. These results provide a foundation for future studies aimed at both increasing enzyme potency and antibacterial activity.
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影响因子：
3.1
作者：
Dale, SE;Doherty-Kirby, A;Heinrichs, DE
通讯作者：
Heinrichs, DE
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
2.8
作者：
Dorsey, CW;Tolmasky, ME;Actis, LA
通讯作者：
Actis, LA
影响因子：
3.1
作者：
Gaddy, Jennifer A.;Arivett, Brock A.;Actis, Luis A.
通讯作者：
Actis, Luis A.
影响因子：
2.8
作者：
Dorsey, CW;Tomaras, AP;Actis, LA
通讯作者：
Actis, LA