Model-based integration of genomics and metabolomics reveals SNP functionality in <i>Mycobacterium tuberculosis</i>

Significance Because genetic diversity in the Mycobacterium tuberculosis complex (MTBC) is less pronounced than in other pathogens, the variable outcome of infection has been attributed mainly to host and environmental factors. Here, we reveal widely different metabolic phenotypes among MTBC members, suggesting that strain diversity may play an important role during infection. To unravel the genetic basis for metabolic diversity, we developed a approach that integrates metabolomic and genomic data for 18 MTBC clinical strains. Our approach allowed us to investigate the metabolic effect of rare genetic variants and to predict mutations that associate with strain-specific metabolic vulnerabilities and inherent baseline susceptibility to antibiotics. Our model-based approach is broadly applicable to many organisms, opening possibilities for identifying more selective treatment strategies.