A Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Anti-Mycobacterial Activity.

Uday S Ganapathy,Mónica Cacho-Izquierdo,Rubén González Del Rio,Joël Lelièvre,Thomas Dick,Martin Gengenbacher,David Barros-Aguirre,Fátima Ortega,Véronique Dartois,Marissa Lindman

doi:10.1128/aac.02420-20

Abstract

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.

Highlights

Global infections by nontuberculous mycobacteria (NTM) are steadily rising
While GSK656 was active against M. abscessus Bamboo, this compound had no activity against M. avium 11 (Table 1)
Since composition of the medium and the presence of detergents can affect potency [33, 34], we measured the MIC of EC/11770 in cation-adjusted Mueller-Hinton (CAMH) broth, which is the clinical standard for antibiotic susceptibility testing, has a different carbon source composition from 7H9, and lacks detergent [35]

Summary

Introduction

Global infections by nontuberculous 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. 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 antimycobacterials. Treatment of M. abscessus lung disease, involves a combination of a macrolide with parenterally administered antibiotics, typically an aminoglycoside and either imipenem, cefoxitin, or tigecycline as a third drug. The fact that M. abscessus chemotherapy requires intravenous drug administration is another complicating factor not encountered in M. avium treatment, in which all drugs can be administered orally. In both cases, treatment typically lasts 18 to 24 months, produces severe drug side effects, and drives acquired drug resistance. De novo drug discovery campaigns remain largely absent due to their higher attrition rates compared to those of repurposing strategies, making them slower and costlier endeavors

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Results

Conclusion