Structural and enzymatic analyses reveal the binding mode of a novel series of Francisella tularensis enoyl reductase (FabI) inhibitors.
Structural and enzymatic analyses reveal the binding mode of a novel series of Francisella tularensis enoyl reductase (FabI) inhibitors.
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DOI：
10.1021/jm300489v
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发表时间：
2012-06-28
影响因子：
7.3
通讯作者：
Johnson, Michael E.
中科院分区：
文献类型：
--
作者：
Mehboob, Shahila;Hevener, Kirk E.;Truong, Kent;Boci, Teuta;Santarsiero, Bernard D.;Johnson, Michael E.
由于真核生物和原核生物脂肪酸合成酶之间的结构和机制差异，细菌途径FAS-II是设计抗微生物剂的有吸引力的目标。我们以前已经报道了一系列新的苯并咪唑化合物的鉴定，这些化合物对A类生物战病原体土拉弗朗西斯菌具有特别好的抗菌效果。本文报道了F.土拉热菌FabI酶与我们最具活性的与NADH结合的苯并咪唑化合物复合。该结构揭示了苯并咪唑化合物以不同于其他已知FabI抑制剂的结合基序的独特构象结合至底物位点。详细的抑制动力学已经证实，该化合物具有一种新的抑制机制，这是独特的已知FabI抑制剂。这些研究可能对未来的抗菌设计工作产生重大影响，并可能揭示FAS-II活性抗菌化合物设计的新途径。
Due to structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motif of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.
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影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Bartlett, John
通讯作者：
Bartlett, John
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
4.1
作者：
Marrakchi, H;DeWolf, WE;Wallis, NG
通讯作者：
Wallis, NG
影响因子：
5.2
作者：
England, Kathleen;Ende, Christopher Am;Slayden, Richard A.
通讯作者：
Slayden, Richard A.
影响因子：
7.3
作者：
GRASSBERGER, MA;TURNOWSKY, F;HILDEBRANDT, J
通讯作者：
HILDEBRANDT, J