Open AccessA Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Antimycobacterial Activity
Author(s) -
Uday S. Ganapathy,
Rubén González del Río,
Mónica Cacho-Izquierdo,
Fátima Ortega,
Joël Lelièvre,
David Barros-Aguirre,
Marissa Lindman,
Véronique Dartois,
Martin Gengenbacher,
Thomas Dick
Publication year - 2021
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.02420-20
Subject(s) - antimycobacterial , nontuberculous mycobacteria , repurposing , broad spectrum , antibiotics , mycobacterium avium complex , medicine , biology , microbiology and biotechnology , pharmacology , virology , tuberculosis , mycobacterium , chemistry , mycobacterium tuberculosis , pathology , ecology , combinatorial chemistry
Global infections by non-tuberculous mycobacteria (NTM) are steadily rising. New drugs are needed to treat NTM infections, but the NTM drug pipeline remains poorly populated and focused on repurposing or reformulating approved antibiotics. We sought to accelerate de novo NTM drug discovery by testing advanced compounds with established activity against Mycobacterium tuberculosis 3-aminomethyl 4-halogen benzoxaboroles, a novel class of leucyl-tRNA synthetase inhibitors, were recently discovered as active against M. tuberculosis Here, we report that the benzoxaborole EC/11770 is not only a potent anti-tubercular agent but is active against the M. abscessus and M. avium complexes. Focusing on M. abscessus , which causes the most difficult-to-cure NTM disease, we show that EC/11770 retained potency against drug-tolerant biofilms in vitro and was effective in a mouse lung infection model. Resistant mutant selection experiments showed a low frequency of resistance and confirmed leucyl-tRNA synthetase as the target. This work establishes the benzoxaborole EC/11770 as a novel preclinical candidate for the treatment of NTM lung disease and tuberculosis and validates leucyl-tRNA synthetase as an attractive target for the development of broad-spectrum anti-mycobacterials.