The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy
- Institute of Genomics and Integrative Biology, India
Abstract
A prolonged therapy, primarily responsible for development of drug resistance by Mycobacterium tuberculosis (Mtb), obligates any new TB regimen to not only reduce treatment duration but also escape pathogen resistance mechanisms. With the aim of harnessing the host response in providing support to existing regimens, we used sertraline (SRT) to stunt the pro-pathogenic type I IFN response of macrophages to infection. While SRT alone could only arrest bacterial growth, it effectively escalated the bactericidal activities of Isoniazid (H) and Rifampicin (R) in macrophages. This strengthening of antibiotic potencies by SRT was more evident in conditions of ineffective control by these frontline TB drug, against tolerant strains or dormant Mtb. SRT, could significantly combine with standard TB drugs to enhance early pathogen clearance from tissues of mice infected with either drug sensitive/ tolerant strains of Mtb. Further, we demonstrate an enhanced protection in acute TB infection of the highly susceptible C3HeB/FeJ mice with the combination therapy signifying the use of SRT as a potent adjunct to standard TB therapeutic regimens against bacterial populations of diverse physiology. This study advocates a novel host directed adjunct therapy regimen for TB with a clinically approved anti-depressant to achieve quicker and greater control of infection.
Data availability
This manuscript does not include any sequencing or high through put data. Also this work does not include any protein crystallization and diffraction analysis. The manuscript does not involve data for submission to depositing datasets into a domain-specific public archive.
Article and author information
Author details
Funding
Council of Scientific and Industrial Research, India (BSC0123)
- Vivek Rao
Council of Scientific and Industrial Research, India (OLP0136)
- Vivek Rao
Indian Council of Medical Research (GAP0213)
- Vivek Rao
Council of Scientific and Industrial Research, India (STS0016)
- Vivek Rao
Council of Scientific and Industrial Research, India (MLP2106)
- Vivek Rao
Council of Scientific and Industrial Research, India (MLP2012)
- Vivek Rao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations of the Control and Supervision of Experiments on Animals (CPCSEA). Experiments were conducted in line with approved protocols of the Institutional animal ethics committee, CSIR- IGIB (IGIB/IAEC/OCT2018/10, IGIB/IAEC/13/28/2020).
Human subjects: The study was conducted in strict accordance with recommendations of the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, Indian Council of Medical Research (ICMR), Government of India. The protocols followed were approved by the Institutional human ethics committee of IGIB, proposal no 10, 2016 and Ref no: CSIR-IGIB/IHEC/2017-18 Dt. 08.02.2018. Patient informed consent was obtained prior to commencing the work.
Copyright
© 2023, Shankaran et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy
eLife 12:e64834.
https://doi.org/10.7554/eLife.64834
