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

Sherine E Thomas,Andrew J Whitehouse,Tom L Blundell,Jasper Sangen,Sophie Burbaud,Anthony G Coyne,Juan M Belardinelli,Rodrigo Andres Floto,Chris Abell,Vítor Mendes,Helena I M Boshoff,Karen Brown,Ramanuj Lahiri,Mary Jackson,Pooja Gupta,Sony Malhotra,Mark Daben J Libardo

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.

Highlights

Mycobacteria are a group of diverse organisms that include many important human pathogens such as Mycobacterium tuberculosis, responsible for over 1.5 million deaths per year from tuberculosis and Mycobacterium leprae, the causative agent of leprosy, both associated with increasing rates of acquired drug resistance [1,2]
Previous transposon mutagenesis studies have suggested that trmD is essential in M. tuberculosis [46,47,48], confirmation of essentiality in M. abscessus was previously lacking
We have focused on targeting TrmD (tRNA-(N(1)G37) methyltransferase), an essential tRNA modification enzyme in bacteria that methylates the guanosine base at position 37 of tRNAs containing G36G37 bases at the anti-codon region to prevent frame-shifting

Summary

Introduction

Mycobacteria are a group of diverse organisms that include many important human pathogens such as Mycobacterium tuberculosis, responsible for over 1.5 million deaths per year from tuberculosis and Mycobacterium leprae, the causative agent of leprosy, both associated with increasing rates of acquired drug resistance [1,2]. Mycobacterium abscessus is intrinsically resistant to most existing antibiotics and as a consequence infections are associated with extremely high rates of treatment failure and mortality [5]. Several structurally diverse, modified nucleosides found at different locations of tRNAs help in the maintenance of the reading frame and avoidance of translational frameshift errors. Many such nucleoside modifications are found in regions near the anticodon, at position 34 (the wobble position) and 37 (3 and adjacent to the anticodon) of tRNA [6,7]. TrmD, tRNA-(N(1)G37) methyltransferase, catalyzes the methylation of G37

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Conclusion