Detection of a bedaquiline / clofazimine resistance reservoir in Mycobacterium tuberculosis predating the antibiotic era

Abstract

AbstractDrug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by resistance-associated variants (RAVs) in the Rv0678 gene which can also confer cross-resistance to clofazimine, another TB drug. We compiled a dataset of 3,682 Mtb genomes, including 223 carrying Rv0678 bedaquiline RAVs. We identified at least 15 cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic analyses point to multiple emergence events and in some cases widespread circulation of RAVs in Rv0678, often prior to the introduction of bedaquiline or clofazimine. Strikingly, this included three cases predating the antibiotic era. The presence of a pre-existing reservoir of bedaquiline-resistant Mtb strains necessitates the urgent implementation of rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.