The relative transmission fitness of multidrug-resistant Mycobacterium tuberculosis in a drug resistance hotspot

Chloé Loiseau, Etthel M. Windels (), Sebastian M. Gygli, Levan Jugheli, Nino Maghradze, Daniela Brites, Amanda Ross, Galo Goig, Miriam Reinhard, Sonia Borrell, Andrej Trauner, Anna Dötsch, Rusudan Aspindzelashvili, Rebecca Denes, Klaus Reither, Christian Beisel, Nestani Tukvadze, Zaza Avaliani, Tanja Stadler and Sebastien Gagneux ()
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Chloé Loiseau: Swiss Tropical and Public Health Institute
Etthel M. Windels: ETH Zürich
Sebastian M. Gygli: Swiss Tropical and Public Health Institute
Levan Jugheli: Swiss Tropical and Public Health Institute
Nino Maghradze: Swiss Tropical and Public Health Institute
Daniela Brites: Swiss Tropical and Public Health Institute
Amanda Ross: Swiss Tropical and Public Health Institute
Galo Goig: Swiss Tropical and Public Health Institute
Miriam Reinhard: Swiss Tropical and Public Health Institute
Sonia Borrell: Swiss Tropical and Public Health Institute
Andrej Trauner: Swiss Tropical and Public Health Institute
Anna Dötsch: Swiss Tropical and Public Health Institute
Rusudan Aspindzelashvili: National Center for Tuberculosis and Lung Diseases (NCTLD)
Rebecca Denes: ETH Zürich
Klaus Reither: Swiss Tropical and Public Health Institute
Christian Beisel: ETH Zürich
Nestani Tukvadze: Swiss Tropical and Public Health Institute
Zaza Avaliani: National Center for Tuberculosis and Lung Diseases (NCTLD)
Tanja Stadler: ETH Zürich
Sebastien Gagneux: Swiss Tropical and Public Health Institute

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Multidrug-resistant tuberculosis (MDR-TB) is among the most frequent causes of death due to antimicrobial resistance. Although only 3% of global TB cases are MDR, geographical hotspots with up to 40% of MDR-TB have been observed in countries of the former Soviet Union. While the quality of TB control and patient-related factors are known contributors to such hotspots, the role of the pathogen remains unclear. Here we show that in the country of Georgia, a known hotspot of MDR-TB, MDR Mycobacterium tuberculosis strains of lineage 4 (L4) transmit less than their drug-susceptible counterparts, whereas most MDR strains of L2 suffer no such defect. Our findings further indicate that the high transmission fitness of these L2 strains results from epistatic interactions between the rifampicin resistance-conferring mutation RpoB S450L, compensatory mutations in the RNA polymerase, and other pre-existing genetic features of L2/Beijing clones that circulate in Georgia. We conclude that the transmission fitness of MDR M. tuberculosis strains is heterogeneous, but can be as high as drug-susceptible forms, and that such highly drug-resistant and transmissible strains contribute to the emergence and maintenance of hotspots of MDR-TB. As these strains successfully overcome the metabolic burden of drug resistance, and given the ongoing rollout of new treatment regimens against MDR-TB, proper surveillance should be implemented to prevent these strains from acquiring resistance to the additional drugs.

Date: 2023
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DOI: 10.1038/s41467-023-37719-y

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