Understanding Mycobacterium tuberculosis evolution in times of antibiotic treatment – A whole genome approach

Aims and objectives Resistant-, multidrug resistant- (MDR) and even extensively drug resistant- (XDR) Mycobacterium tuberculosis complex (MTBC) strains have emerged worldwide and represent a serious challenge for global tuberculosis (TB) control. Interestingly, high rates of MDR TB have been associated with particular phylogenetic lineages of the MTBC such as the Beijing lineage and the strong clonal expansion of particular MDR strains in Eastern Europe. However, a systematic investigation of the evolution and cross border transmission of particular highly transmissible MDR strains in Eastern Europe has not been performed so far. Methods To address this question, an in-depth analysis was performed of the population structure (based on 24 loci MIRU-VNTR-typing and spoligotyping) of strains from different settings in Eastern Europe, such as Uzbekistan, Turkmenistan, and Kazakhstan. Results The results showed that two major clones of the Beijing lineage are the drivers of the MDR epidemic in Eastern Europe. In addition, retrospective investigation of an MDR strain collection from Germany using MIRU-VNTR and IS 6110 RFLP patterns revealed that both clones were circulating for more than 15 years. In-depth analysis of genome characteristics confirmed the longitudinal transmission of the two major MDR clones and allowed the identification of particular beneficial combinations of mutations potentially compensating for the fitness defect of the MDR/XDR strains. Moreover, these allele combinations coincide with an enhanced transmissibility compared with other circulating MDR/XDR strain types and promote the selection of extremely drug resistant but also highly virulent MTBC strain variants. Conclusion Taken together, these data argue strongly for an expansion of particular MDR Beijing clones in Eastern Europe that started at least 15 years ago. Evolution and selection over the past years has resulted in “hyper transmissible” MDR-TB strains that have the potential to spread rapidly and, thus, further complicate TB control.