TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus

Abstract

Lung disease caused by Mycobacterium abscessus is very difficult to cure, and treatment failure rates are high. The antituberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays a long terminal half-life, and presents a cardiotoxicity liability associated with QT interval prolongation. Recent medicinal chemistry campaigns resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ which are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, a clinical development candidate of this series, shows attractive in vitro antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 is active against M. abscessus. TBAJ-876 displayed submicromolar in vitro activity against reference strains representing the three subspecies of M. abscessus and against a collection of clinical isolates. Drug-drug potency interaction studies with commonly used anti-M. abscessus antibiotics showed no antagonistic effects, suggesting that TBAJ-876 could be coadministered with currently used drugs. Efficacy studies, employing a mouse model of M. abscessus infection, demonstrated potent activity in vivo. In summary, we demonstrate that TBAJ-876 shows attractive in vitro and in vivo activities against M. abscessus, similar to its BDQ parent. This suggests that next-generation BDQ, with improved tolerability and pharmacological profiles, may be useful for the treatment of M. abscessus lung disease in addition to the treatment of tuberculosis.

Differential In Vitro Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved Mycobacterium abscessus

“…Sarathy et al reported in vitro additivity between rifabutin and bedaquiline by checkerboard assay against M. abscessus subsp. abscessus strain Bamboo in 7H9 broth, with MIC readings (based on optical density) of 3.6 and 0.8 µg/mL for rifabutin alone and combined with bedaquiline, respectively; however, bactericidal activity could not be assessed using this assay method (40). Interestingly, Dick et al…”

A Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Antimycobacterial Activity

“…Second, we prioritize the screening of advanced compounds. With established pharmacokinetics (PK) and tolerability, advanced compounds circumvent several critical hurdles in de novo drug discovery, allowing them to move rapidly from in vitro NTM actives to lead compounds with demonstrated in vivo efficacy (20). Amino-acyl tRNA synthetases (aaRSs) are enzymes that correctly attach each amino acid to its cognate tRNA molecule, enabling proper translation of the genetic code (21).…”

Differentialin vitroactivity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starvedMycobacterium abscessus

“…Sarathy et al reported in vitro additivity between rifabutin and bedaquiline by checkerboard assay against M. abscessus subsp. abscessus strain Bamboo in 7H9 broth, with MIC readings (based on optical density) of 3.6 and 0.8 μg/mL for rifabutin alone and combined with bedaquiline, respectively; however, bactericidal activity could not be assessed using this assay method (40). Interestingly, Dick et al recently reported that rifabutin alone had significant in vivo bactericidal activity against M. abscessus subsp.…”