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

Scheme showing supposed molecular key events in mycobacterial evolution from a recombinogenic M. canettii strain pool toward professional pathogens of mammalian hosts. Network phylogeny inferred among eight M. canettii strains and 46 selected genome sequences from MTBC members by NeighborNet analysis. Pairwise alignments of whole genome SNP data are the basis of the calculation. Recombination of pks5 and deletion of pap in a potential progenitor of the MTBC strains illustrated in the inset. Figure reproduced from reference 44 .

Neighbor-joining phylogeny scheme based on variable nucleotide positions with main focus on tubercle bacilli that have a human host preference, using M. canettii as root of the tree (after reference 56 ). The filtered SNPs refer to the mutations identified between the various strains relative to M. tuberculosis H37Rv ( 15 ). Figure reproduced from reference 40 .

Overview of a large number of potential drug resistance as well as compensatory mutations against first- and second-line drugs. Mutations shown in bold represent most commonly found mutations among resistant strains. Semibold secondary mutations in rpoB, rpoC, and rpoB were found to be shared by related strains, thus suggesting mutations favoring transmission. Any mutations leading to at least rifampin and isoniazid resistance confer an MDR phenotype, whereas MDR strains with additional mutations against at least one of the three injectable drugs, kanamycin, amikacin, and capreomycin, and to any fluoroquinolone used against M. tuberculosis are referred to as XDR strains. Table based on mutations found in the following publications ( 50 , 58 , 73 , 89 , 91 , 92 , 130 , 133 , 142 , 143 , 149 , 151 – 154 , 156 , 163 , 166 ).

Overview of a large number of potential drug resistance as well as compensatory mutations against first- and second-line drugs. Mutations shown in bold represent most commonly found mutations among resistant strains. Semibold secondary mutations in rpoB, rpoC, and rpoB were found to be shared by related strains, thus suggesting mutations favoring transmission. Any mutations leading to at least rifampin and isoniazid resistance confer an MDR phenotype, whereas MDR strains with additional mutations against at least one of the three injectable drugs, kanamycin, amikacin, and capreomycin, and to any fluoroquinolone used against M. tuberculosis are referred to as XDR strains. Table based on mutations found in the following publications ( 50 , 58 , 73 , 89 , 91 , 92 , 130 , 133 , 142 , 143 , 149 , 151 – 154 , 156 , 163 , 166 ).

Suggested model for a selection bottleneck followed by random mutations on the population structure of M. tuberculosis clinical isolates. Genetic diversity of subpopulations is present in a rifampin monoresistant clinical M. tuberculosis isolate (each individual bacterium contains a rifampin resistance-conferring mutation). Upon isoniazid treatment clones carrying low-cost resistance mutations to the drug become dominant and prevail over other variants, resulting in the loss of numerous other genetic mutations. Subsequent repeated genetic diversification results in genomic heterogeneity of the MDR strain population. x represents an isoniazid resistance-causing mutation. Figure adapted from reference 163 .