Abstract
Multidrug-resistant tuberculosis (MDR-TB) accounts for one third of the annual deaths due to antimicrobial resistance1. Drug resistance-conferring mutations frequently cause fitness costs in bacteria2,3,4,5. Experimental work indicates that these drug resistance-related fitness costs might be mitigated by compensatory mutations6,7,8,9,10. However, the clinical relevance of compensatory evolution remains poorly understood. Here we show that, in the country of Georgia, during a 6-year nationwide study, 63% of MDR-TB was due to patient-to-patient transmission. Compensatory mutations and patient incarceration were independently associated with transmission. Furthermore, compensatory mutations were overrepresented among isolates from incarcerated individuals that also frequently spilled over into the non-incarcerated population. As a result, up to 31% of MDR-TB in Georgia was directly or indirectly linked to prisons. We conclude that prisons fuel the epidemic of MDR-TB in Georgia by acting as ecological drivers of fitness-compensated strains with high transmission potential.
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Data availability
The raw sequences were deposited at the European Nucleotide Archive under BioProject ID PRJEB39561. Accession numbers are listed in Supplementary Table 2. Metadata associated with the genomes are provided in Supplementary Table 2.
Change history
01 June 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41591-021-01417-3
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Acknowledgements
Calculations were performed at the sciCORE (http://scicore.unibas.ch/) scientific computing core facility at the University of Basel. We would like to thank D. Klinkenberg (Dutch National Institute for Public Health and the Environment) for help with the phybreak analysis and D. Brites for feedback on the manuscript. We also thank J. Andrews and the two other anonymous reviewers for their excellent comments that helped us improve our manuscript. Funding: This work was supported by the Swiss National Science Foundation (grants 310030_188888, IZRJZ3_164171, IZLSZ3_170834 and CRSII5_177163, all to S.G.), the European Research Council (309540-EVODRTB and 883582-ECOEVODRTB, both to S.G.) and SystemsX.ch (to S.G. and C.B.).
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S.G. and L.J. conceived the idea. S.G. and Z.A. supervised the project. S.M.G. performed data curation, data analysis and wrote the first draft. C.L. performed data curation and data analysis. L.J. supervised data acquisition and curation. N.A., R.A., M.R. and N.M. carried out data acquisition. A.T. and A.R. carried out data analysis. S.B. supervised data acquisition. K.R. critically reviewed the drafts. C.B. and N.T. supervised data acquisition. All authors reviewed the draft and assisted in the manuscript preparation.
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Peer review information Nature Medicine thanks Jason Andrews and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Editor recognition statement: Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Supplementary Results; Supplementary Tables 1, 3, 5, 6, 8 and 14–19; Supplementary References; and Supplementary Figs. 1–8.
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Supplementary Tables 2, 4, 7 and 9–13
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Gygli, S.M., Loiseau, C., Jugheli, L. et al. Prisons as ecological drivers of fitness-compensated multidrug-resistant Mycobacterium tuberculosis. Nat Med 27, 1171–1177 (2021). https://doi.org/10.1038/s41591-021-01358-x
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DOI: https://doi.org/10.1038/s41591-021-01358-x
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