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 de-repress 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., 2-8× 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.

Next-generation diarylquinolines improve sterilizing activity of regimens with pretomanid and the novel oxazolidinone TBI-223 in a mouse tuberculosis model

“…Thus, S587 added bactericidal activity to PaL, even at the lowest dose (5 mg/kg) tested. At 7.6 mg/kg S587 was equivalent to bedaquiline at 25 mg/kg while S587 at 25 mg/kg was superior to bedaquiline at 25 mg/kg, as reported previously by Xu et al (4).…”

“…One major finding of this study is that two novel DARQs currently in Phase 1 clinical trials exhibited superior sterilizing activity when substituted for bedaquiline at the same (S587) or lower (S876) doses in the BPaL regimen. These results significantly extend prior observations (3, 4) of improved bactericidal activity with these DARQs to demonstrate their treatment-shortening potential compared to bedaquiline. In a prior study, S587 exhibited greater bactericidal activity than bedaquiline in this mouse model, including against infection with an Rv0678 ( mmpR5 ) mutant with reduced susceptibility to DARQs and prevented the development of resistance in wild-type M. tuberculosis as well as additional pretomanid resistance in the mmpR5 mutant (4).…”

“…These results significantly extend prior observations (3, 4) of improved bactericidal activity with these DARQs to demonstrate their treatment-shortening potential compared to bedaquiline. In a prior study, S587 exhibited greater bactericidal activity than bedaquiline in this mouse model, including against infection with an Rv0678 ( mmpR5 ) mutant with reduced susceptibility to DARQs and prevented the development of resistance in wild-type M. tuberculosis as well as additional pretomanid resistance in the mmpR5 mutant (4). Similarly, S876 had superior activity compared to bedaquiline and was active in vitro and in vivo at much lower doses, e.g., 6.25 mg/kg rather than 25 mg/kg (3).…”

“…Indeed, two next-generation diarylquinoline (DARQ) drugs with more potent activity than bedaquiline are now in phase 1 clinical trials, TBAJ-587 (S587) and TBAJ-876 (S876), (ClinicalTrials.gov identifiers: NCT04890535 and NCT04493671, respectively). We recently used a well-established BALB/c mouse infection model of TB to demonstrate the superior bactericidal activity of novel regimens in which either new DARQ is used in place of bedaquiline in the BPaL regimen (3, 4). The newer DARQs also retained greater activity against isogenic strains with reduced bedaquiline susceptibility due to mutations in the mmpL5/mmpS5 repressor, Rv0678 (also known as mmpR5 ).…”

The role of epistasis in amikacin, kanamycin, bedaquiline, and clofazimine resistance in Mycobacterium tuberculosis complex

“…If confirmed, this should also apply to mmpS5 - mmpL5 LoF mutants with wild-type mmpR (e.g. just over half of the lineage 1.1.1.1 isolates in our dataset had a nonsense mutation in mmpL5 ) and may have implications for the ongoing trials of TBAJ-876, TBAJ-587, TBI-166, and OPC-167832 as these agents are also exported by this pump (Hariguchi et al, 2020; Xu et al, 2021, 2019).…”