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
Further reading
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- Medicine
- Microbiology and Infectious Disease
Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
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- Microbiology and Infectious Disease
Sirtuins are the major players in host immunometabolic regulation. However, the role of sirtuins in the modulation of the immune metabolism pertaining to salmonellosis is largely unknown. Here, our investigation focussed on the role of two important sirtuins, SIRT1 and SIRT3, shedding light on their impact on intracellular Salmonella’s metabolic switch and pathogenesis establishment. Our study indicated the ability of the live Salmonella Typhimurium to differentially regulate the levels of SIRT1 and SIRT3 for maintaining the high glycolytic metabolism and low fatty acid metabolism in Salmonella. Perturbing SIRT1 or SIRT3 through knockdown or inhibition resulted in a remarkable shift in the host metabolism to low fatty acid oxidation and high glycolysis. This switch led to decreased proliferation of Salmonella in the macrophages. Further, Salmonella-induced higher levels of SIRT1 and SIRT3 led to a skewed polarization state of the macrophages from a pro-inflammatory M1 state toward an immunosuppressive M2, making it more conducive for the intracellular life of Salmonella. Alongside, governing immunological functions by modulating p65 NF-κB acetylation, SIRT1, and SIRT3 also skew Salmonella-induced host metabolic switch by regulating the acetylation status of HIF-1α and PDHA1. Interestingly, though knockdown of SIRT1/3 attenuated Salmonella proliferation in macrophages, in in vivo mice model of infection, inhibition or knockdown of SIRT1/3 led to more dissemination and higher organ burden, which can be attributed to enhanced ROS and IL-6 production. Our study hence reports for the first time that Salmonella modulates SIRT1/3 levels to maintain its own metabolism for successful pathogenesis.
