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S85 Bedaquiline resistance in Mycobacterium tuberculosis predates its clinical use
  1. C Nimmo1,
  2. L van Dorp1,
  3. A Torres Ortiz1,
  4. J Pang1,
  5. M Acman1,
  6. J Millard2,
  7. N Padayatchi3,
  8. A Grant4,
  9. M O’Donnell4,
  10. O Brynildsrud5,
  11. V Eldholm5,
  12. L Grandjean1,
  13. X Didelot6,
  14. F Balloux1
  1. 1University College London, London, UK
  2. 2Wellcome Trust Liverpool Glasgow Centre for Global Health Research, Liverpool, UK
  3. 3Centre for AIDS Programme of Research in South Africa, Durban, South Africa
  4. 4London School of Hygiene and Tropical Medicine, London, UK
  5. 5Norwegian Institute of Public Health, Oslo, Norway
  6. 6University of Warwick, Coventry, UK

Abstract

Background Bedaquiline has become a key drug for treatment of drug-resistant tuberculosis. Most clinical resistance is conferred by mutations in Rv0678, a negative repressor of the MmpL5 efflux pump, and confer clofazimine cross-resistance. Here, we estimate the date of emergence of several Rv0678 variants in global Mycobacterium tuberculosis lineages.

Methods We constructed global whole genome sequence datasets of thousands of lineage 2 and 4 isolates using newly generated and publicly available data. We enriched these by screening public repositories for sequences containing all previously reported Rv0678 variants. We built a whole genome maximum likelihood phylogenetic tree using RAxML-Ng and dated the nodes of this phylogeny using BEAST. The lineage 2 dataset contained 1514 sequences from isolates collected between 1994–2019. The lineage 4 dataset contained 2168 sequences including three from 18th century mummies.

Results We identified 483 non-synonymous and promoter variants in 439 sequences. 25 sequences were from isolates collected prior to bedaquiline clinical trials in 2007 and 21 of these contained bedaquiline resistance-associated variants. Most Rv0678 mutations occurred in sequences carrying other resistance variants.

In lineage 2 we identify 58 unique emergences of resistance estimated to have occurred between 1988–2018 (figure 1), of which 40 were represented by a single genome. In lineage 4 we identify 85 unique emergences estimated to have occurred between 1701–2019 (figure 1), of which 59 were represented by a single genome. We also identified a clade of 65 samples carrying the Ile67fs variant that we estimated to have arisen in 1701 (1657–1732). This predates the first use of clofazimine or bedaquiline.

Abstract S85 Figure 1

Estimated age of emergence of Rv0678 nonsynonymous variants.Inferred point estimates for the dates of clades with Rv0678 variants for the lineage 2 (a) and lineage 4 (b) datasets. Predicted Rv0678 phenotype is given by the colour as defined in the legend at bottom.

Conclusions Rv0678 mutations conferring bedaquiline/clofazimine resistance have been in circulation since before the antibiotic era, implying non-synonymous mutations in Rv0678 have little fitness cost. This pre-existing reservoir of resistant strains is likely to expand with increasing bedaquiline and clofazimine use.

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