Comprehensive characterization of Rv0678 bedaquiline resistance-conferring polymorphisms

ABSTRACT Bedaquiline is central to nearly all shorter, modernized all-oral regimens being evaluated and is revolutionizing rifampin-resistant tuberculosis treatment. Yet, despite extensive research activity in this space, a poor understanding of the genotype-phenotype correlation (i.e., the association between specific mutations (genotype) and the resulting spectrum of resistance) is the primary barrier to developing an accurate molecular diagnostic for bedaquiline. We propose accelerating discovery in this area using an unbiased, comprehensive mutational and screening strategy to determine the range and scope of all rv0678 mutations conferring bedaquiline resistance. We will construct a library of M. tuberculosis clones carrying single-nucleotide polymorphisms and specific indels, and we will screen this library in vitro and in a murine model. The success of our proposed work will provide a template to accelerate the discovery of resistance-conferring variants for all new and repurposed agents and help close the diagnostic gap, allowing for the development of tests to rapidly inform treatment decisions, regardless of resource setting.