Development of Inhibitors against Mycobacterium abscessus tRNA (m(1)G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

Whitehouse Andrew J.; Thomas Sherine E.; Brown Karen P.; Fanourakis Alexander; Chan Daniel S. -H.; Libardo M. Daben J.; Mendes Vitor; Boshoff Helena I. M.; Floto R. Andres; Abell Chris; Blundell Tom L.; Coyne Anthony G.

首页> 外文期刊>Journal of Medicinal Chemistry >Development of Inhibitors against Mycobacterium abscessus tRNA (m(1)G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

【24h】

Development of Inhibitors against Mycobacterium abscessus tRNA (m(1)G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

机译：利用基于片段的方法，抑制抑制剂对脓肿性脓肿TRNA（M（1）G37）甲基转移酶（TRMD）的抑制剂

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相似文献
相关主题

摘要

Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontubercu ous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.

机译：分枝杆菌脓肿（MAB）是一种迅速生长的多药抗性Nontubercu的种类，它被出现为对囊性纤维化和其他预先存在的慢性肺病的个体的巨大威胁。 MAB肺部感染是难度的，或有时不可能，治疗和导致加速肺功能下降和过早死亡。因此，迫切需要开发新的抗生素，具有改善的疗效。 TRNA（M1G37）甲基转移酶（TRMD）是新型抗生素的有希望的靶标。它在MAB和其他分枝杆菌中至关重要，改善了核糖体上的阅读框架维护，以防止颤动误差。在这项工作中，采用基于片段的方法，其与活性位点结合的两个片段的合并，然后进行结构引导的培训，以设计针对MAB TRMD的有效的纳米摩尔抑制剂。这些化合物中的几种表现出对细菌物种的有希望的活性，包括结核分枝杆菌和麻痹性Leprae除了MAB之外，支持使用TRMD作为开发抗微生物化合物的靶标。

著录项

来源
《Journal of Medicinal Chemistry》 |2019年第15期|共23页
作者
Whitehouse Andrew J.; Thomas Sherine E.; Brown Karen P.; Fanourakis Alexander; Chan Daniel S. -H.; Libardo M. Daben J.; Mendes Vitor; Boshoff Helena I. M.; Floto R. Andres; Abell Chris; Blundell Tom L.; Coyne Anthony G.;
展开▼
作者单位

Univ Cambridge Dept Chem Lensfield Rd Cambridge CB2 1EW England;

Univ Cambridge Dept Biochem Tennis Court Rd Cambridge CB2 1GA England;

Univ Cambridge MRC Lab Mol Biol Mol Immun Unit Dept Med Francis Crick Ave Cambridge Biomed Campus Cambridge CB2 0QH England;

Univ Cambridge Dept Chem Lensfield Rd Cambridge CB2 1EW England;

Univ Cambridge Dept Chem Lensfield Rd Cambridge CB2 1EW England;

NIAID TB Res Sect Lab Clin Immunol &

Microbiol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

Univ Cambridge Dept Biochem Tennis Court Rd Cambridge CB2 1GA England;

NIAID TB Res Sect Lab Clin Immunol &

Microbiol NIH 9000 Rockville Pike Bethesda MD 20892 USA;

Univ Cambridge MRC Lab Mol Biol Mol Immun Unit Dept Med Francis Crick Ave Cambridge Biomed Campus Cambridge CB2 0QH England;

Univ Cambridge Dept Chem Lensfield Rd Cambridge CB2 1EW England;

Univ Cambridge Dept Biochem Tennis Court Rd Cambridge CB2 1GA England;

Univ Cambridge Dept Chem Lensfield Rd Cambridge CB2 1EW England;

展开▼
收录信息
原文格式 PDF
正文语种 eng
中图分类药学;
关键词

相似文献

外文文献
中文文献
专利

1. Development of Inhibitors against Mycobacterium abscessus tRNA (m(1)G37) Methyltransferase (TrmD) Using Fragment-Based Approaches [J] . Whitehouse Andrew J., Thomas Sherine E., Brown Karen P., Journal of Medicinal Chemistry . 2019,第15期

机译：利用基于片段的方法，抑制抑制剂对脓肿性脓肿TRNA（M（1）G37）甲基转移酶（TRMD）的抑制剂
2. Mutations in MetG (methionyl-tRNA synthetase) and TrmD [tRNA (guanine-N1)-methyltransferase] conferring meropenem tolerance in Burkholderia thailandensis [J] . Yi Hyojeong, Lee Hyeri, Cho Kwang-Hwi, The Journal of Antimicrobial Chemotherapy . 2018,第2期

机译：MetG（甲硫醇-TRNA合成酶）和TRMD [TRMD [TRNA（鸟嘌呤-N1） - 甲基转移酶]赋予Meropenem耐受性在Burkowneria泰国人群中的突变
3. The Temperature Sensitivity of a Mutation in the Essential tRNA Modification Enzyme tRNA Methyltransferase D (TrmD) [J] . Isao Masuda, Reiko Sakaguchi, Cuiping Liu, The Journal of biological chemistry . 2013,第40期

机译：基本TRNA改性酶TRNA甲基转移酶D（TRMD）中突变的温度敏感性
4. Combining combinatorial chemistry and affinity chromatographic for systematically probing protein-ligand interactions:application to the development of highly selective inhibitors of human betaine:homocysteine S-methyltransferase [C] . Michaela Collinsova, Carmen Castro, Timothy A.Garrow, European Peptide Symposium . 2002

机译：组合化学和亲和力色谱法系统探测蛋白 - 配体相互作用：应用于人甜菜碱的高选择性抑制剂的应用：同型半胱氨酸S-甲基转移酶
5. Analyses of mRNA Cleavage by RelE and the Role of tRNA Methyltransferase TrmD Using Bacterial Ribosome Profiling [D] . Hwang, Jae Yeon 2016

机译：细菌核糖体谱分析RelE对mRNA的切割及tRNA甲基转移酶TrmD的作用
6. Development ofInhibitors against Mycobacteriumabscessus tRNA (m1G37) Methyltransferase(TrmD) Using Fragment-Based Approaches [O] . AndrewJ. Whitehouse, Sherine E. Thomas, Karen P. Brown, -1

机译：的发展抗分枝杆菌的抑制剂脓肿tRNA（m1G37）甲基转移酶（TrmD）使用基于片段的方法
7. Development of Inhibitors Against Mycobacterium Abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches [O] . Andrew J. Whitehouse, Sherine E. Thomas, Karen P. Brown, 2019

机译：使用基于片段的方法的抑制剂对脓肿性脓肿TRNA（M1G37）甲基转移酶（TRMD）的抑制剂的发展

Development of Inhibitors against Mycobacterium abscessus tRNA (m(1)G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

摘要

著录项

相似文献

相关主题

期刊订阅