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

• Published in: Nucleic acids research Vol. 48; no. 14; pp. 8099 - 8112
• Main Authors: Thomas, Sherine E, Whitehouse, Andrew J, Brown, Karen, Burbaud, Sophie, Belardinelli, Juan M, Sangen, Jasper, Lahiri, Ramanuj, Libardo, Mark Daben J, Gupta, Pooja, Malhotra, Sony, Boshoff, Helena I M, Jackson, Mary, Abell, Chris, Coyne, Anthony G, Blundell, Tom L, Floto, Rodrigo Andres, Mendes, Vítor
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 20.08.2020
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Binding Sites; Drug Discovery - methods; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Molecular Docking Simulation; Mycobacterium abscessus - drug effects; Mycobacterium abscessus - enzymology; Mycobacterium leprae - drug effects; Mycobacterium leprae - enzymology; Protein Binding; RNA, Transfer - metabolism; Structural Biology; tRNA Methyltransferases - antagonists & inhibitors; tRNA Methyltransferases - chemistry; tRNA Methyltransferases - metabolism
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkaa539

Abstract 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.