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

Jian Xu,Eric L Nuermberger,Paul J Converse,Khisimuzi Mdluli,Anna M Upton,Nader Fotouhi

doi:10.1128/aac.02418-20

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.

Highlights

Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis
The results indicate that replacing BDQ in these regimens with TBAJ-587 could increase their efficacy against wild-type M. tuberculosis as well as Rv0678 mutants and reduce the emergence of resistance to diarylquinolines and companion drugs
The experimental schemes indicating the regimens used against the wild-type strain, M. tuberculosis H37Rv, and an isogenic mutant with an IS6110 insertion in the Rv0678 gene are given in Tables S1 and S2 in the supplemental material, respectively

Summary

Introduction

Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. A novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Novel regimens based on the backbone of BDQ and pretomanid (PMD) have shown the potential to significantly shorten the duration of treatment of MDR/XDR-TB as well as drug-susceptible (DS) TB [14, 15], as predicted by studies in mice [16, 17]. Coupled with evidence that Rv0678 variants with reduced BDQ susceptibility have been isolated from MDR-TB patients without known prior exposure to BDQ or clofazimine [19, 23, 24], these reports raise concern that emergence of Rv0678 variants could undermine the promising clinical efficacy of BDQ-containing regimens. Mutation of Rv0678 reduces the in vitro activity of TBAJ-587 to a similar degree as BDQ, TBAJ-587 remains more potent than BDQ against such mutants and may be more effective at killing them or preventing their selection during treatment [26]

Methods

Results

Conclusion