Discovery of antimicrobial agent targeting tryptophan synthase

文献类型： 外文期刊

第一作者： Bosken, Yuliana K.

作者： Bosken, Yuliana K.;Ai, Rizi;Hilario, Eduardo;Kan, Shih-Hsin;Mueller, Leonard J.;Chang, Chia-En A.;Ghosh, Rittik K.;Dunn, Michael F.;Niks, Dimitri;Fan, Li;Zhou, Huanbin;Ma, Wenbo;Kan, Shih-Hsin;Zhou, Huanbin;Ma, Wenbo

作者机构：

关键词： antimicrobial agents; computer-aided drug discovery; crystal structure; enzyme inhibitor; essential bacterial pathway; molecular docking; structure-based drug discovery; virtual screening

期刊名称：PROTEIN SCIENCE （ 影响因子：6.725； 五年影响因子：4.316 ）

ISSN： 0961-8368

年卷期：

页码：

收录情况： SCI

摘要： Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug-resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure-based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the alpha subunit of tryptophan synthase with experimental methods involving the whole-cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L-tryptophan biosynthesis. Screening 1,800 compounds from the National Cancer Institute Diversity Set I against alpha subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that a one successful inhibitor, 3-amino-3-imino-2-phenyldiazenylpropanamide (Compound 1) binds to the alpha subunit. We also report a crystal structure of Salmonella enterica serotype Typhimurium tryptophan synthase in complex with Compound 1 which revealed a binding site at the alpha beta interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development.

分类号：

  • 相关文献
作者其他论文 更多>>

微信小程序