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Evolutionary history of extensive antibiotic resistance in Mycobacterium tuberculosis

At the origin of 1.5 million deaths each year, tuberculosis is a leading cause of death due to an infectious disease, only surpassed by COVID in 2020-2021. A study based on genomic sequencing has determined the bacterial factors and certain historical events involved in the emergence and international spread of multidrug-resistant strains. These results, published in Nature Communications, highlight the need to deploy new means of detecting extended resistance.

Phylogenetic tree based on the sequencing of the genomes of 720 W148 strains and 12 related external strains. The different colored circles show, from the inside out, the presence (full box) or absence (empty box) of mutations conferring resistance to different drugs (INH isoniazid, SM streptomycin, RIF rifampicin, EMB ethambutol, PZA pyrazinamide, FQ fluoroquinolones, KM kanamycin, ETH ethionamide and PAS para-aminosalicylic acid), the associated antibiotic resistance profiles (XDR extensive resistance and pre-XDR pre- extensive resistance), and the presence of compensatory mutations. Groups of epidemic variants particularly localized in Belarus and Estonia are indicated.

Multi-/extensively drug resistant (MDR/XDR) tuberculosis, mostly driven by human-to-human transmission, is the leading cause of human death due to antimicrobial resistance. Particular branches of a lineage of Mycobacterium tuberculosisstrains are responsible for the high prevalence of multidrug resistance in Eurasia, and show exceptional transnational distributions. Dr Philip Supply’s research group at the CIIL, together with other French and German scientists, have determined the factors underlying the emergence and epidemic spread of the branch called W148 by analyzing the genomes of more than 700 strains from 23 countries. The results date a common ancestor already resistant to isoniazid and streptomycin to the early 1960s, consistent with the introduction of these antibiotics at that time. Successive epidemic expansions followed in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet era. These strains evolved to (pre-)XDR levels in less than two decades, accumulating resistance mutations to up to 11 drugs. Transmission of the most resistant strains is associated with the acquisition of mutations compensating the metabolic cost due to resistance mutations. All W148 strains also possess a hypervirulence mutation, and some of them have acquired additional mutations that may further promote the development of additional resistance.

This exceptional genetic arsenal and the wide geographical distribution of these strains constitute a "perfect storm", jeopardizing the success of the introduction of new treatments for MDR tuberculosis. The deployment on a larger scale of new tests with an extended diagnostic spectrum, such as the Deeplex Myc-TB test recently developed by GenoScreen with the assistance of Dr Philip Supply, will be essential to combat the spread of such highly resistant strains.


Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis.

Merker M, Rasigade JP, Barbier M, Cox H, Feuerriegel S, Kohl TA, Shitikov E, Klaos K, Gaudin C, Antoine R, Diel R, Borrell S, Gagneux S, Nikolayevskyy V, Andres S, Crudu V, Supply P, Niemann S, Wirth T.

Nat Commun. 2022 13:5105. doi: 10.1038/s41467-022-32455-1