Journal
REDOX BIOLOGY
Volume 15, Issue -, Pages 452-466Publisher
ELSEVIER
DOI: 10.1016/j.redox.2017.12.020
Keywords
Mycobacterium tuberculosis; Vitamin C; Dormancy; Viable but non-culturable; Heterogeneous subpopulations; TB drugs; Antibiotic tolerance
Categories
Funding
- Department of Biotechnology, Government of India [BT/01/CEIB/10/III/04]
- Department of Science and Technology, Government of India
- Council of Scientific and Industrial Research, Government of India
- Department of Science and Technology, Government of India [PDF/2016/000745, YSS/2015/000562/LS]
- Department of Biotechnology, Government of India
- Department of Science and Technology, Government of India for DST-INSPIRE Faculty fellowship
- Wellcome Trust/DBT India Alliance [IA/CPHE/14/1/501504]
- Wellcome trust-DBT India Alliance [IA/S/16/2/502]
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Bacterial dormancy is a major impediment to the eradication of tuberculosis (TB), because currently used drugs primarily target actively replicating bacteria. Therefore, decoding of the critical survival pathways in dormant tubercle bacilli is a research priority to formulate new approaches for killing these bacteria. Employing a network-based gene expression analysis approach, we demonstrate that redox active vitamin C (vit C) triggers a multifaceted and robust adaptation response in Mycobacterium tuberculosis (Mtb) involving similar to 67% of the genome. Vit C-adapted bacteria display well-described features of dormancy, including growth stasis and progression to a viable but non-culturable (VBNC) state, loss of acid-fastness and reduction in length, dissipation of reductive stress through triglyceride (TAG) accumulation, protective response to oxidative stress, and tolerance to first line TB drugs. VBNC bacteria are reactivatable upon removal of vit C and they recover drug susceptibility properties. Vit C synergizes with pyrazinamide, a unique TB drug with sterilizing activity, to kill dormant and replicating bacteria, negating any tolerance to rifampicin and isoniazid in combination treatment in both in-vitro and intracellular infection models. Finally, the vit C multi-stress redox models described here also offer a unique opportunity for concurrent screening of compounds/combinations active against heterogeneous subpopulations of Mtb. These findings suggest a novel strategy of vit C adjunctive therapy by modulating bacterial physiology for enhanced efficacy of combination chemotherapy with existing drugs, and also possible synergies to guide new therapeutic combinations towards accelerating TB treatment.
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