The Mycobacterium tuberculosis genome at 25 years: lessons and lingering questions

Abstract

First achieved in 1998 by Cole et al., the complete genome sequence of Mycobacterium tuberculosis continues to provide an invaluable resource to understand tuberculosis (TB), the leading cause of global infectious disease mortality. At the 25-year anniversary of this accomplishment, we describe how insights gleaned from the M. tuberculosis genome have led to vital tools for TB research, epidemiology, and clinical practice. The increasing accessibility of whole-genome sequencing across research and clinical settings has improved our ability to predict antibacterial susceptibility, to track epidemics at the level of individual outbreaks and wider historical trends, to query the efficacy of the bacille Calmette-Guérin (BCG) vaccine, and to uncover targets for novel antitubercular therapeutics. Likewise, we discuss several recent efforts to extract further discoveries from this powerful resource.

Refined understanding of the impact of the Mycobacterium tuberculosis complex diversity on the intrinsic susceptibility to pretomanid

“…L6, which causes up to half of TB in some West African countries yet appears underrepresented among rifampicin-resistant strains, was more susceptible than L5 and L2–4/7 and should, therefore, respond better to BPaL(M) ( 3 , 24 ). More MICs are needed for L8, L9, and the different animal-adapted MTBC genotypes (e.g., Mycobacterium bovis ), and it would be desirable to clarify their likely response to BPaL(M), although this is not a priority as these are much rarer than L1–7 ( 3 , 14 , 24 ).…”

“…The goal of this study was twofold. First, we used MGIT to refine the current understanding of the effect of the MTBC diversity on susceptibility, with a particular focus on the less frequent lineage 5 (L5), lineage 6 (L6), lineage 7 (L7), lineage 8 (L8), and lineage 9 (L9) that were not tested or were underrepresented in the literature ( 3 , 13 , 14 ). Second, we used Middlebrook 7H11 (7H11) as an alternative medium to investigate whether the differences observed with MGIT were media specific.…”