Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification

被引：18

作者：

Thomas, Sherine E. ^{[1
]}

Whitehouse, Andrew J. ^{[2
]}

Brown, Karen ^{[3
,4
]}

Burbaud, Sophie ^{[3
]}

Belardinelli, Juan M. ^{[5
]}

Sangen, Jasper ^{[3
]}

Lahiri, Ramanuj ^{[6
]}

Libardo, Mark Daben J. ^{[7
]}

Gupta, Pooja ^{[1
]}

Malhotra, Sony ^{[8
]}

Boshoff, Helena I. M. ^{[7
]}

Jackson, Mary ^{[5
]}

Abell, Chris ^{[2
]}

Coyne, Anthony G. ^{[2
]}

Blundell, Tom L. ^{[1
]}

Floto, Rodrigo Andres ^{[3
,4
]}

Mendes, Vitor ^{[1
]}

机构：

[1] Univ Cambridge, Dept Biochem, 80 Tennis Court Rd, Cambridge CB2 1GA, England

[2] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England

[3] MRC Lab Mol Biol, Univ Cambridge Mol Immun Unit, Francis Crick Ave, Cambridge CB2 0QH, England

[4] Royal Papworth Hosp, Cambridge Ctr Lung Infect, Cambridge CB2 0AY, England

[5] Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA

[6] Healthcare Syst Bur, Hlth Resources & Serv Adm, Dept Hlth & Human Serv, Natl Hansens Dis Program, Baton Rouge, LA USA

[7] NIAID, TB Res Sect, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[8] Univ London, Birkbeck Coll, Malet St, London WC1E 7HX, England

来源：

NUCLEIC ACIDS RESEARCH | 2020年 / 48卷 / 14期

基金：

英国工程与自然科学研究理事会; 英国惠康基金;

关键词：

TRNASCAN-SE; TUBERCULOSIS; LEPRAE; PREVENTION; INFECTION; GENES; TRMD;

D O I：

10.1093/nar/gkaa539

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.

引用

页码：8099 / 8112

页数：14

共 58 条

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