TY - JOUR
T1 - Comparative efficacy of the novel diarylquinoline TBAJ-876 and Bedaquiline against a Resistant Rv0678 Mutant in a mouse model of tuberculosis
AU - Almeida, Deepak
AU - Converse, Paul
AU - Li, Si Yang
AU - Upton, Anna M.
AU - Fotouhi, Nader
AU - Nuermberger, Eric L.
N1 - Funding Information:
This research was supported by TB Alliance with support from Australia Aid, the Bill and Melinda Gates Foundation, the Germany Federal Ministry of Education and Research through KfW, Global Health Innovative Technology Fund, Irish Aid, Netherlands Ministry of Foreign Affairs, and UK Aid.
Publisher Copyright:
Copyright © 2021 Almeida et al.
PY - 2021/12
Y1 - 2021/12
N2 - Bedaquiline (BDQ, B) is the first-in-class diarylquinoline to be approved for treatment of tuberculosis (TB). Recent guidelines recommend its use in treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). The newly approved regimen combining BDQ with pretomanid and linezolid is the first 6-month oral regimen proven to be effective against MDR/XDR-TB. However, the emergence of BDQ resistance, primarily due to inactivating mutations in the Rv0678 gene encoding a repressor of the MmpS5-MmpL5 transporter, threatens to undermine the efficacy of new BDQ-containing regimens. Since the shift in MIC due to these mutations is relatively small (2-8×), safer, and more potent, diarylquinoline analogues may be more effective than BDQ. TBAJ-876, which is in phase 1 trials, has more potent in vitro activity and a superior pre-clinical safety profile than BDQ. Using a murine model of TB, we evaluated the dose-dependent activity of TBAJ-876 compared to BDQ against the wildtype H37Rv strain and an isogenic Rv0678 loss-of-function mutant. Although the mutation affected the MIC of both drugs, the MIC of TBAJ-876 against the mutant was 10- fold lower than that of BDQ. TBAJ-876 at doses ≥6.25 mg/kg had greater efficacy against both strains compared to BDQ at 25 mg/kg, when administered alone or in combination with pretomanid and linezolid. Likewise, no selective amplification of BDQ-resistant bacteria was observed at TBAJ-876 doses ≥6.25 mg/kg. These results indicate that replacing BDQ with TBAJ-876 may shorten the duration of TB treatment and be more effective in treating and preventing infections caused by Rv0678 mutants.
AB - Bedaquiline (BDQ, B) is the first-in-class diarylquinoline to be approved for treatment of tuberculosis (TB). Recent guidelines recommend its use in treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). The newly approved regimen combining BDQ with pretomanid and linezolid is the first 6-month oral regimen proven to be effective against MDR/XDR-TB. However, the emergence of BDQ resistance, primarily due to inactivating mutations in the Rv0678 gene encoding a repressor of the MmpS5-MmpL5 transporter, threatens to undermine the efficacy of new BDQ-containing regimens. Since the shift in MIC due to these mutations is relatively small (2-8×), safer, and more potent, diarylquinoline analogues may be more effective than BDQ. TBAJ-876, which is in phase 1 trials, has more potent in vitro activity and a superior pre-clinical safety profile than BDQ. Using a murine model of TB, we evaluated the dose-dependent activity of TBAJ-876 compared to BDQ against the wildtype H37Rv strain and an isogenic Rv0678 loss-of-function mutant. Although the mutation affected the MIC of both drugs, the MIC of TBAJ-876 against the mutant was 10- fold lower than that of BDQ. TBAJ-876 at doses ≥6.25 mg/kg had greater efficacy against both strains compared to BDQ at 25 mg/kg, when administered alone or in combination with pretomanid and linezolid. Likewise, no selective amplification of BDQ-resistant bacteria was observed at TBAJ-876 doses ≥6.25 mg/kg. These results indicate that replacing BDQ with TBAJ-876 may shorten the duration of TB treatment and be more effective in treating and preventing infections caused by Rv0678 mutants.
KW - Bedaquiline
KW - Linezolid
KW - Mouse
KW - Mycobacterium tuberculosis
KW - Pretomanid
KW - Resistance
KW - TBAJ-876
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85119379421&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119379421&partnerID=8YFLogxK
U2 - 10.1128/AAC.01412-21
DO - 10.1128/AAC.01412-21
M3 - Article
C2 - 34570644
AN - SCOPUS:85119379421
SN - 0066-4804
VL - 65
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 12
M1 - e01412-21
ER -