Compensatory evolution drives multidrug-resistant tuberculosis in Central Asia

Merker, M.; Barbier, M.; Cox, H.; Rasigade, J.-P.; Feuerriegel, S.; Kohl, T. A.; Diel, R.; Borrell, S.; Gagneux, S.; Nikolayevskyy, V.; Andres, S.; Nübel, U.; Supply, P.; Wirth, T.; Niemann, S.

doi:10.1101/334599

bioRxiv · 10.1101/334599

Compensatory evolution drives multidrug-resistant tuberculosis in Central Asia

Merker, M.·Barbier, M.·Cox, H.·Rasigade, J.-P.·Feuerriegel, S.·Kohl, T. A.·Diel, R.·Borrell, S.·Gagneux, S.·Nikolayevskyy, V.·Andres, S.·Nübel, U.·Supply, P.·Wirth, T.·Niemann, S.

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Abstract

Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear.\n\nWe utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR-MTBC strains from Karakalpakstan, Uzbekistan (2001-2006).\n\nOne MTBC-clone (termed Central Asian outbreak, CAO) with resistance mediating mutations to eight anti-TB drugs existed prior the worldwide introduction of standardized WHO-endorsed directly observed treatment, short-course (DOTS). DOTS implementation in Karakalpakstan in 1998 likely selected for these CAO-strains, comprising 75% of sampled MDR-TB strains in 2005/2006. CAO-strains were also identified in a previously published cohort from Samara, Russia (2008-2010). Similarly, transmission success and resistance development was linked to mutations compensating fitness deficits associated with rifampicin resistance.\n\nThe genetic make-up of these outbreak clades threatens the success of both empirical and standardized guideline driven MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.

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Merker, M., Barbier, M., Cox, H., Rasigade, J.-P., Feuerriegel, S., Kohl, T. A., Diel, R., Borrell, S., Gagneux, S., Nikolayevskyy, V., Andres, S., Nübel, U., Supply, P., Wirth, T., Niemann, S.. 2018-05-31. Compensatory evolution drives multidrug-resistant tuberculosis in Central Asia. https://doi.org/10.1101/334599

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