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Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches.

Abstract：

:Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Whitehouse AJ,Thomas SE,Brown KP,Fanourakis A,Chan DS,Libardo MDJ,Mendes V,Boshoff HIM,Floto RA,Abell C,Blundell TL,Coyne AG

doi

10.1021/acs.jmedchem.9b00809

subject

Has Abstract

pub_date

2019-08-08 00:00:00

pages

7210-7232

issue

15

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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