Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

Abstract

Certain aminoacyl-tRNA synthetases developed a proofreading mechanism to ensure aminoacylation of tRNAs with cognate amino acids. Epetraborole (EPT) was identified as an inhibitor of the leucyl-tRNA synthetase (LeuRS) editing site in Mycobacterium abscessus. EPT displayed enhanced activity against M. abscessus over Mycobacterium tuberculosis. Crystallographic and equilibrium binding data showed that EPT binds LeuRSMabs and LeuRSMtb with similar Kd. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed the non-proteinogenic amino acid norvaline, leucine residues in proteins were replaced by norvaline, inducing expression of GroEL chaperonins and Clp proteases. In vitro data revealed that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis. The combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection.