Evolution of Mycobacterium tuberculosis: New Insights into Pathogenicity and Drug Resistance

The evolution of Mycobacterium tuberculosis toward one of the most dangerous human pathogens is of particular interest for the analysis of the continued importance of tuberculosis as a global disease. While the majority of mycobacterial species are harmless environmental bacteria, M. tuberculosis is able to induce pulmonary lesions and disease in the human host, which represents an essential step for the aerosol transmission of the bacterium to new individuals. The question of when and where M. tuberculosis or one of its progenitors has acquired this faculty has interested scientists for years. It is hypothesized that the ancestors of M. tuberculosis once had an environmental reservoir and gradually evolved to adapt to the life within host cells, leading finally to the feature of getting transmitted from one host to another ( 1 , 2 ). First insights into this issue can be obtained from genomic comparison of M. tuberculosis with related nontuberculous mycobacteria (NTM), also known as atypical mycobacteria or mycobacteria other than tuberculosis (MOTT). Based on 16S rRNA sequence similarity, Mycobacterium marinum and Mycobacterium ulcerans were the currently known closest relatives of M. tuberculosis ( 3 ). In a later study, based on whole-genome sequencing (WGS), Mycobacterium kansasii was found as the closest NTM species of M. tuberculosis ( 4 ), whereas a different WGS study designated M. marinum/M. ulcerans as most closely related to M. tuberculosis, followed by a subgroup containing Mycobacterium haemophilum, Mycobacterium lepromatosis, and Mycobacterium leprae ( 5 ). However, despite the similarities at the DNA and protein level, the genome size differences between the closest NTM species relative to M. tuberculosis are considerable ( 6 ). M. tuberculosis strains harbor a 4.4 MB genome ( 7 – 9 ), whereas the genomes of M. marinum, M. kansasii, and M. ulcerans are larger in size (6.7, 6.4, and 5.8 MB, respectively) ( 10 – 12 ). In contrast, the genomes of M. haemophilum, M. lepromatosis, and M. leprae are smaller in size (4.2, 3.3, and 3.3 MB, respectively) ( 5 , 13 , 14 ), whereby the strong size reduction of the latter two species is due to a common, extensive phase of reductive evolution ( 13 ). It seems conceivable that the individual adaptations of the different mycobacterial species to specific environmental conditions went along with genome downsizing, gene acquisition through horizontal gene transfer, genome rearrangements, and/or recombination.