Tuberculosis treatment failure associated with evolution of antibiotic resilience
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.
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.).Additional details
- Eprint ID
- 118746
- Resolver ID
- CaltechAUTHORS:20230105-911538600.9
- P01 AI132130
- NIH
- RFA-AI-21-065
- NIH
- P01 AI143575
- NIH
- R01 AI143611-01
- NIH
- Created
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2023-02-07Created from EPrint's datestamp field
- Updated
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2023-02-07Created from EPrint's last_modified field