Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification
S.E. Thomas, Andrew Whitehouse, Karen Brown, Sophie Burbaud, Juan M. Belardinelli, Jasper Sangen, Ramanuj Lahiri, M. Daben J. Libardo, Pooja Gupta, Sony Malhotra, Helena I. Boshoff, Mary Jackson, Chris Abell, Anthony G. Coyne, Tom L. Blundell, R. Andrés Floto, V. Mendes
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.