DTI Drug Target Insights 2024; 18: 27-29 ISSN 1177-3928 | DOI: 10.33393/dti.2024.3076 EDITORIAL Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti © 2024 The Authors. This article is published by AboutScience and licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.aboutscience.eu Tuberculosis research: Quo vadis Nerges F. Mistry The Foundation for Medical Research, Dr. Kantilal J. Sheth Memorial Building, Mumbai - India Received: March 26, 2024 Accepted: May 14, 2024 Published online: May 31, 2024 Corresponding author: Nerges F. Mistry email: fmr@fmrindia.org/fmrmum@gmail.com against the TB bacillus. From rifampicin in the early 1970s to bedaquiline (BDQ) and delamanid in 2012 and 2013, the trickle of new drugs is envisaged as a powerful means of dis- ease control but one that has a window of time before drug resistance sets in for a single drug/drug combination. One of the most singular findings in recent years is the theme that resistance to any drug can occur even before the drug is put to use by the disease programme. Extensive drug-resistant TB was detected in KwaZulu Natal even before the same drugs were deployed, through natural selection (9). Similarly in a cohort in India, mutations bestowing high minimum inhibitory concentrations (MICs) to BDQ such as Rv0678: c.141_142dupTC, p.Glu55Asp, p.Leu117Arg, p.Gly162Glu; atpE: p.Glu61Asp, p.Thr51Ile, p.Ser37Ala; pepQ: p.Pro69Leu, p.Arg7Gln; mmpL5: Ile948Val, Thr794Ile, Asp767Asn (FMR unpublished data) were seen in patients not exposed to BDQ. Does the presence of such natural mutations signify a natu- ral tendency for resistance amplification? This is a powerful phenomenon to study the evolution of drug resistance in the coming years. Another paradigm has been the linkage of gut microbi- ome to the phenomenon of drug resistance in an individual (10). Modulating the microbiome towards greater diversity and speciation offers a novel way to combat the emergence of drug resistance that needs to be explored with incisive studies, especially since a disturbed gut microbiome contin- ues to exist for over 1.2 years post-anti-TB treatment (11). The use of complex compounds in phytomedicine indicates another approach to minimizing drug resistance. These com- plex structures in plant products may retard the development of drug resistance to conventional anti-TB drugs by stabilizing the gut microbiome or may have anti-bacterial action directly vs drug-resistant bacteria. This would provide a relatively cost-effective approach to the treatment of drug-resistant TB. Though no scattered studies provide positive indications (12-14), rigorous in-depth research is required. Diagnosis TB is well recognized as a respiratory disease spread through the air through microdroplets, especially in vulner- able communities. The ability to capture and detect such infectious droplets through masks (15,16) or through capture chambers (17) has given a profound scenario of disease biol- ogy. Increasing evidence has been generated in very recent years in even non-symptomatic individuals where disease in the preclinical stages shows the capture of such infectious droplets (18). This leads to a paradigm change in understand- ing the transmission of TB through non-symptomatic individ- uals, say, within a household in vulnerable communities and Despite 142 years of ongoing research, since Robert Koch discovered the tuberculosis (TB) bacillus, TB continues to flourish in the most vulnerable parts of the globe in Asia, Africa and South America (1). Indeed, progressive socio- economic measures (nutrition, housing and environment) have shown to be more effective than research in disease elimination in affluent areas of the globe (2). Undoubtedly, however, areas undertaken in recent research studies under- score new knowledge that may yield far-reaching impact on disease control, if not elimination. This editorial aims to high- light such specific studies and their impact. Non-medical determinants Little attention was paid to research on socio-economic measures. In this regard, two studies, viz., Bhargava et al. (3) and Shin et al. (4), stand out. Additionally, McKeown’s famous graph (5) showed a dramatic decrease in TB even in the absence of drugs with good housing and a balanced diet. With the recent RATIONS (Reducing Activation of Tuberculosis by Improvement of Nutritional Status) trial in rural Jharkhand, the problem of undernutrition as a primary cause of TB was brought into the limelight though with nutrition supplementation only 54% of patients reached the desirable weight gain at 2 months of treatment (6). This poses several puzzling questions which need to be answered to establish nutrition as an effective control/ prevention tool. Environmental pollution studies and its effect on TB incidence are also gaining ground with emphasis on par- ticulate matter 2.5 and even smaller particles (7). However, the concept of healthy housing with optimal access to light and ven- tilation has been overlooked in India though it is prevalent in some countries of South-East Asia (8). In a study in the slums in Mumbai air exchange of 1-2 every 13 hours was seen to be the norm as opposed to the desired 6-7 per hour (FMR unpublished study). Transmission of all respiratory diseases is inevitable and will be continuous with such a large ventilation deficit and will continue to take place with compromised ventilation. Drugs and mutations The most singular outcome of biomedical research in TB has been to identify new and repurposed drugs for use https://doi.org/10.33393/dti.2024.3076 https://doi.org/dti.2022.2522 https://creativecommons.org/licenses/by-nc/4.0/legalcode mailto:fmr@fmrindia.org mailto:fmrmum@gmail.com TB Research: Quo vadis28 © 2024 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti which can also be utilized effectively during active prevalence surveys. The pipeline of novel TB diagnostics has never been richer. Several large consortia funded by the United States Agency for International Development, National Institutes of Health and Unitaid are currently undertaking validation study of these diagnostics for ensuring that the best are put to use. The future will stress self-sampling and self-testing technolo- gies, which are likely to have wider acceptability. Surveillance The epidemiological research in TB is likely to be trans- formed in the coming years through increasing use of sur- veillance methods be it for antimicrobial resistance (AMR), mutations, clinical profiles or drug responses. The ability of countries to sustain continued data collection and rapid analysis would allow the use of key data that can be used for disease control. Genomic surveillance and questions on how the environ- ment fashions Mycobacterium tuberculosis (M.tb) response could not have occurred without the explosion in the field of bioinformatic tools and their application. For instance, Fastlin facilitates ultra-fast and accurate mycobacterium complex lineage typing, whereas Mykrobe can predict AMR in min- utes (19,20). MTBseq is a comprehensive pipeline developed for whole-genome sequencing of M.tb complex isolates (21). These have been invaluable in ascertaining strain differences and in detecting transmission of TB in hyperendemic areas or examining tissue tropism of strain in extrapulmonary TB. We anticipate the generation of crucial knowledge in the coming years through deciphering the language of the cells. Operations research In operations research, the engagement of the private sector has become a key theme in recent times taken up on a global basis through the formation of public-private learn- ing networks led by McGill University in Toronto. The Public Private Interface Agency (PPIA) introduced by the Gates Foundation in India around 2015 showed some early gains for patients accessing a PPIA-engaged physician at the first point of call (22). Whether this has translated to its successor, the Private Provider Support Agency (PPSA) overseen by the Government of India, remains to be evaluated. The PPSA as of now is run on bureaucratic rather than functional lines, the emphasis being on orienting non-govern- mental organizations (the middle link between the National Tuberculosis Elimination Programme and the community) rather than sensitization and education of private sector phy- sicians. The PPSA needs evaluation to fine-tune a potentially effective solution to early diagnosis, correct treatment and follow-up of TB patients buoyed by support mechanisms of direct cash benefit transfer for nutrition to patients. The pioneering differentiated care model introduced by the Indian state of Tamil Nadu in 2022-2023 (23) is an innovative step today open for wider dissemination nation- ally and globally. It takes into account severe undernutri- tion, impaired lung function and overall functionality. This model if researched well will provide crucial learnings on approaches to reducing mortality and enhancing patient care infrastructure. An excessively strict adherence to national guidelines for disease control paradoxically retards innovative insights in clinical and microbiological research and also adversely affects patient outcomes. Structures must be instituted to examine result discrepancies so that new paradigms of knowledge can be created. Encouraging a comprehensive and open approach With an eye on equitable access to knowledge and treat- ment, research should increasingly focus on to what extent and circumstances users stay out of the service technology net. The upfront GeneXpert (24) initiative and the SMaRT-PCR initiative (25 and Online) in diagnostic technology validation is a step in the right direction where technical performance is supplemented with an inquiry into community-level accept- ability and feasibility. Two areas of applicability of such an approach are paediatric TB and post-treatment rehabilita- tion, an area almost completely ignored today in India. The next couple of years will give a comprehensive view of how novel technologies need to be translated for field conditions. With the advent of big data technology globally, there comes the responsibility of open data sharing that can ward off common global threats. The trend of overt protection of country data needs to be eschewed if the common good is to be realized by the use of big data. Such global cooperation is a desirable but still yet distant goal. Abbreviations TB, tuberculosis; BDQ, bedaquiline; M.tb, Mycobacterium tuberculosis; PPIA, Public Private Interface Agency; PPSA, Private Provider Support Agency Acknowledgements Grateful thanks to Dr. Ambreen Shaikh and Ms. Poonam Daswani at The Foundation for Medical Research for their assistance in referencing for this editorial. Disclosures Conflict of Interest: The author has no conflict of interest to declare. Funding: The research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References 1. World Health Organization (WHO). Global tuberculosis report, 2023. Online. Accessed 21 February 2024. 2. McKeown T, Record RG. Reasons for the decline of mortality in England and Wales during the nineteenth century. Population Studies. 1962;16(2):94-122. CrossRef 3. Bhargava A, Pai M, Bhargava M, Marais BJ, Menzies D. Can social interventions prevent tuberculosis?: The Papworth experiment (1918-1943) revisited. Am J Respir Crit Care Med. 2012;186(5):442-449. CrossRef PubMed https://fmrindia.org/tuberculosis.html https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023 https://doi.org/10.1080/00324728.1962.10414870 https://doi.org/10.1164/rccm.201201-0023OC https://www.ncbi.nlm.nih.gov/pubmed/22773730 Mistry Drug Target Insights 2024; 18: 29 © 2024 The Authors. Published by AboutScience - www.aboutscience.eu 4. Shin S, Furin J, Bayona J, Mate K, Kim JY, Farmer P. Community- based treatment of multidrug-resistant tuberculosis in Lima, Peru: 7 years of experience. Soc Sci Med. 2004;59(7):1529- 1539. CrossRef PubMed 5. McKeown T. The modern rise of population. Edward Arnold; 1976. 6. Bhargava A, Bhargava M, Meher A, et al. Nutritional support for adult patients with microbiologically confirmed pulmo- nary tuberculosis: outcomes in a programmatic cohort nested within the RATIONS trial in Jharkhand, India. Lancet Glob Health. 2023;11(9):e1402-e1411. CrossRef PubMed 7. Dimala CA, Kadia BM. A systematic review and meta-analysis on the association between ambient air pollution and pul- monary tuberculosis. Sci Rep. 2022;12(1):11282. CrossRef PubMed 8. Aditama W, Sitepu FY, Saputra R. Relationship between physi- cal condition of house environment and the incidence of pul- monary tuberculosis, Aceh, Indonesia. Int J Sci Health Res. 2019;4(1):227-231. 9. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006;368(9547):1575-1580. CrossRef PubMed 10. Matzaras R, Nikopoulou A, Protonotariou E, Christaki E. Gut microbiota modulation and prevention of dysbiosis as an alter- native approach to antimicrobial resistance: a narrative review. Yale J Biol Med. 2022;95(4):479-494. PubMed 11. Wipperman MF, Fitzgerald DW, Juste MAJ, et al. Antibiotic treatment for tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed. Sci Rep. 2017;7(1):10767. CrossRef PubMed 12. Mangwani N, Singh PK, Kumar V. Medicinal plants: adjunct treatment to tuberculosis chemotherapy to prevent hepatic damage. J Ayurveda Integr Med. 2020;11(4):522-528. CrossRef PubMed 13. Rana HK, Singh AK, Kumar R, Pandey AK. Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(3):1251-1273. CrossRef PubMed 14. Gautam S, Qureshi KA, Jameel Pasha SB, et al. Medicinal plants as therapeutic alternatives to combat Mycobacterium tuberculosis: a comprehensive review. Antibiotics (Basel). 2023;12(3):541. CrossRef PubMed 15. Williams CML, Cheah ESG, Malkin J, et al. Face mask sampling for the detection of Mycobacterium tuberculosis in expelled aerosols. PLoS One. 2014;9(8):e104921. CrossRef PubMed 16. Shaikh A, Sriraman K, Vaswani S, Oswal V, Mistry N. Detection of Mycobacterium tuberculosis RNA in bioaerosols from pul- monary tuberculosis patients. Int J Infect Dis. 2019;86:5-11. CrossRef PubMed 17. Wood R, Morrow C, Barry CE III, et al. Real-time investigation of tuberculosis transmission: developing the respiratory aerosol sampling chamber (RASC). PLoS One. 2016;11(1):e0146658. CrossRef PubMed 18. Williams CM, Abdulwhhab M, Birring SS, et al. Exhaled Myco- bacterium tuberculosis output and detection of subclinical dis- ease by face-mask sampling: prospective observational studies. Lancet Infect Dis. 2020;20(5):607-617. CrossRef PubMed 19. Derelle R, Lees J, Phelan J, Lalvani A, Arinaminpathy N, Chin- delevitch L. fastlin: an ultra-fast program for Mycobacte- rium tuberculosis complex lineage typing. Bioinformatics. 2023;39(11):btad648. CrossRef PubMed 20. Hunt M, Bradley P, Lapierre SG, et al. Antibiotic resistance pre- diction for Mycobacterium tuberculosis from genome sequence data with Mykrobe. Wellcome Open Res. 2019;4:191. CrossRef PubMed 21. Kohl TA, Utpatel C, Schleusener V, et al. MTBseq: a compre- hensive pipeline for whole genome sequence analysis of Myco- bacterium tuberculosis complex isolates. PeerJ. 2018;6:e5895. CrossRef PubMed 22. Shah S, Shah S, Rangan S, et al. Effect of public-private interface agency in Patna and Mumbai, India: does it alter durations and delays in care seeking for drug-sensitive pulmonary tuberculo- sis? Gates Open Res. 2020;4:32. 23. Shewade HD, Frederick A, Kiruthika G, et al. The first differenti- ated TB care model from India: delays and predictors of losses in the care cascade. Glob Health Sci Pract. 2023;11(2):e2200505. CrossRef PubMed 24. Sarin S, Huddart S, Raizada N, et al. Cost and operational impact of promoting upfront GeneXpert MTB/RIF test referrals for presumptive pediatric tuberculosis patients in India. PLoS One. 2019;14(4):e0214675. CrossRef PubMed 25. Shaikh A, Sriraman K, Vaswani S, et al. SMaRT-PCR: sampling using masks and RT-PCR, a non-invasive diagnostic tool for pae- diatric pulmonary TB. Int J Tuberc Lung Dis. 2024;28(4):189- 194. CrossRef PubMed https://doi.org/10.1016/j.socscimed.2004.01.027 https://www.ncbi.nlm.nih.gov/pubmed/15246180 https://doi.org/10.1016/S2214-109X(23)00324-8 https://www.ncbi.nlm.nih.gov/pubmed/37567210 https://doi.org/10.1038/s41598-022-15443-9 https://www.ncbi.nlm.nih.gov/pubmed/35788679 https://doi.org/10.1016/S0140-6736(06)69573-1 https://www.ncbi.nlm.nih.gov/pubmed/17084757 https://www.ncbi.nlm.nih.gov/pubmed/36568836 https://doi.org/10.1038/s41598-017-10346-6 https://www.ncbi.nlm.nih.gov/pubmed/28883399 https://doi.org/10.1016/j.jaim.2019.02.004 https://www.ncbi.nlm.nih.gov/pubmed/31679802 https://doi.org/10.1007/s00210-023-02679-z https://www.ncbi.nlm.nih.gov/pubmed/37665346 https://doi.org/10.3390/antibiotics12030541 https://www.ncbi.nlm.nih.gov/pubmed/36978408 https://doi.org/10.1371/journal.pone.0104921 https://www.ncbi.nlm.nih.gov/pubmed/25122163 https://doi.org/10.1016/j.ijid.2019.06.006 https://www.ncbi.nlm.nih.gov/pubmed/31202909 https://doi.org/10.1371/journal.pone.0146658 https://www.ncbi.nlm.nih.gov/pubmed/26807816 https://doi.org/10.1093/bioinformatics/btad648 https://www.ncbi.nlm.nih.gov/pubmed/32085847 https://doi.org/10.1093/bioinformatics/btad648 https://www.ncbi.nlm.nih.gov/pubmed/37871178 https://doi.org/10.12688/wellcomeopenres.15603.1 https://www.ncbi.nlm.nih.gov/pubmed/32055708 https://doi.org/10.7717/peerj.5895 https://www.ncbi.nlm.nih.gov/pubmed/30479891 https://doi.org/10.9745/GHSP-D-22-00505 https://www.ncbi.nlm.nih.gov/pubmed/37116929 https://doi.org/10.1371/journal.pone.0214675 https://www.ncbi.nlm.nih.gov/pubmed/30933997 https://doi.org/10.5588/ijtld.23.0291 https://www.ncbi.nlm.nih.gov/pubmed/38563336