Journal
SCIENCE
Volume 378, Issue 6624, Pages 1111-1118Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abq2787
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Funding
- National Institutes of Health
- NIH/NIAID
- [P01 AI132130]
- [RFA-AI-21-065]
- [P01 AI143575]
- [R01 AI143611-01]
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The widespread use of antibiotics has put Mycobacterium tuberculosis under pressure to evolve new survival mechanisms. A genomic analysis of clinical isolates has discovered the resR transcriptional regulator and other related factors that are frequently targeted by positive selection. Mutations in these genes are associated with antibiotic resilience and the acquisition of drug resistance.
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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