Liu, Qingyun and Zhu, Junhao and Dulberger, Charles L. and Stanley, Sydney and Wilson, Sean and Chung, Eun Seon and Wang, Xin and Culviner, Peter and Liu, Yue J. and Hicks, Nathan D. and Babunovic, Gregory H. and Giffen, Samantha R. and Aldridge, Bree B. and Garner, Ethan C. and Rubin, Eric J. and Chao, Michael C. and Fortune, Sarah M. (2022) Tuberculosis treatment failure associated with evolution of antibiotic resilience. Science, 378 (6624). pp. 1111-1118. ISSN 0036-8075. doi:10.1126/science.abq2787. https://resolver.caltech.edu/CaltechAUTHORS:20230105-911538600.9
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Abstract
The widespread use of antibiotics has placed bacterial pathogens under intense pressure to evolve new survival mechanisms. Genomic analysis of 51,229 Mycobacterium tuberculosis (Mtb) clinical isolates has identified an essential transcriptional regulator, Rv1830, herein called resR for resilience regulator, as a frequent target of positive (adaptive) selection. resR mutants do not show canonical drug resistance or drug tolerance but instead shorten the post-antibiotic effect, meaning that they enable Mtb to resume growth after drug exposure substantially faster than wild-type strains. We refer to this phenotype as antibiotic resilience. ResR acts in a regulatory cascade with other transcription factors controlling cell growth and division, which are also under positive selection in clinical isolates of Mtb. Mutations of these genes are associated with treatment failure and the acquisition of canonical drug resistance.
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| Additional Information: | We thank T. M. Walker for collecting and sharing information on the geographic origin of >10,000 Mtb isolates and C. M. Sassetti for the helpful discussions during this work. This work was supported by the National Institutes of Health (grants P01 AI132130 and RFA-AI-21-065 to S.M.F., grant P01 AI143575 to S.M.F and E.J.R., and NIH/NIAID grant R01 AI143611-01 to B.B.A.). | ||||||||||||||||||||||||||||||||
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| Issue or Number: | 6624 | ||||||||||||||||||||||||||||||||
| DOI: | 10.1126/science.abq2787 | ||||||||||||||||||||||||||||||||
| Record Number: | CaltechAUTHORS:20230105-911538600.9 | ||||||||||||||||||||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20230105-911538600.9 | ||||||||||||||||||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||||||||||||||||||
| ID Code: | 118746 | ||||||||||||||||||||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||||||||||||||||||||
| Deposited By: | Research Services Depository | ||||||||||||||||||||||||||||||||
| Deposited On: | 07 Feb 2023 20:20 | ||||||||||||||||||||||||||||||||
| Last Modified: | 07 Feb 2023 20:20 |
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