Comparative Efficacy of the Novel Diarylquinoline TBAJ-587 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of Tuberculosis

Abstract

Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that derepress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2 to 8× MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.

Keywords: drug resistance; linezolid; moxifloxacin; pretomanid; pyrazinamide.

FIG 1

TBAJ-587 (S) is more active than bedaquiline (B) either alone or in combination with pretomanid and linezolid (PaL) or pretomanid, moxifloxacin, and pyrazinamide (PaMZ) against wild-type M. tuberculosis. (A) Activity of different regimens during the first month of treatment. (B) Activity of diarylquinoline monotherapy during 2 months of treatment.

FIG 2

TBAJ-587 (S) is more active than bedaquiline (B) either alone or in combination with pretomanid and linezolid (PaL) or pretomanid, moxifloxacin, and pyrazinamide (PaMZ) against M. tuberculosis with an Rv0678 mutation. Activity of the indicated regimens at M1 (A) and M2 (B).