Yes / Objectives: Resistance-associated variants (RAVs) in Rv0678, a regulator of the MmpS5-MmpL5 efflux pump,
have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The
prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors
to take into account in bedaquiline treatment guidelines.
Methods: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding
bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDRTB
sequences of a population-based cohort.
Results: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline
MICs for these isolates were high (>0.24 mg/L, n¼8), normal (0.03 0.24 mg/L, n¼11) or low(<0.03 mg/L, n¼4).
A variant at position 11 in the intergenic region mmpS5–Rv0678 was identified in 39 isolates (11.3%) and appeared
to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/
852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs.
Conclusions: RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated
with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional
breakpoint (0.24mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects
on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility. / This work was supported by Janssen Pharmaceutica. N. C. was supported by a Baekeland PhD scholarship from the Flemish Institute for Scientific Technology (IWT 130308, Belgium). C. J. M., L. R. and B. d. J. were supported by a European Research Council Starting Grant INTERRUPTB (311725).
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/17329 |
| Date | 24 September 2019 |
| Creators | Villellas, C., Coeck, N., Meehan, Conor J., Lounis, N., de Jong, B., Rigouts, L., Andries, K. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| Rights | © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited., CC-BY-NC |
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