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Tuberculosis treatment failure associated with evolution of antibiotic resilience

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.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription
Liu, Qingyun0000-0002-2284-5050
Zhu, Junhao0000-0002-3301-5677
Dulberger, Charles L.0000-0002-1334-5468
Stanley, Sydney0000-0001-6386-2415
Wilson, Sean0000-0002-7216-9804
Chung, Eun Seon0000-0003-4947-4541
Wang, Xin0000-0002-6930-3347
Liu, Yue J.0000-0002-7785-857X
Hicks, Nathan D.0000-0002-6631-8383
Babunovic, Gregory H.0000-0003-4158-6979
Aldridge, Bree B.0000-0003-2236-1424
Garner, Ethan C.0000-0003-0141-3555
Rubin, Eric J.0000-0001-5120-962X
Chao, Michael C.0000-0003-3158-7337
Fortune, Sarah M.0000-0001-7565-9975
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.).
Funding AgencyGrant Number
NIHP01 AI132130
NIHP01 AI143575
NIHR01 AI143611-01
Issue or Number:6624
Record Number:CaltechAUTHORS:20230105-911538600.9
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:118746
Deposited By: Research Services Depository
Deposited On:07 Feb 2023 20:20
Last Modified:07 Feb 2023 20:20

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