Skip to main content
SpringerLink
Log in

Metformin: A Leading HDT Candidate for TB

  • Chapter
  • First Online:
Advances in Host-Directed Therapies Against Tuberculosis

Abstract

Drug-resistance and inadequacies of antimicrobial therapy are barriers to tuberculosis (TB) elimination. Recent interest has focused on the concept of using small molecule drugs to harness endogenous defence mechanisms that could, when combined with anti-tubercular therapy (ATT), tilt the host-pathogen equilibrium in TB lesions towards resolution with minimal tissue damage. Metformin is an ideal candidate for such host-directed therapy (HDT), as it has low cost with an excellent safety profile and low induction of cytochrome p450 (CYP) enzymes. The pleiotropic properties of metformin suggest that the drug acts on multiple tissues through various underlying mechanisms and distinct interacting partners. Here, we discuss the current preclinical and clinical data demonstrating the TB-HDT capability of metformin.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Raviglione MC, Ditiu L (2013) Setting new targets in the fight against tuberculosis. Nat Med 19:263. https://doi.org/10.1038/nm.3129

    Article  CAS  PubMed  Google Scholar 

  2. Wallis RS et al (2016) Tuberculosis-advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers. Lancet Infect Dis 16:e34–e46. https://doi.org/10.1016/S1473-3099(16)00070-0

    Article  CAS  PubMed  Google Scholar 

  3. Gillespie SH et al (2014) Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med 371:1577–1587. https://doi.org/10.1056/NEJMoa1407426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jindani A et al (2014) High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med 371:1599–1608. https://doi.org/10.1056/NEJMoa1314210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nunes-Alves C et al (2014) In search of a new paradigm for protective immunity to TB. Nat Rev Microbiol 12:289–299. https://doi.org/10.1038/nrmicro3230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zumla A, Maeurer M (2012) Rational development of adjunct immune-based therapies for drug-resistant tuberculosis: hypotheses and experimental designs. J Infect Dis 205(Suppl 2):S335–S339. https://doi.org/10.1093/infdis/jir881

    Article  CAS  PubMed  Google Scholar 

  7. Schwegmann A, Brombacher F (2008) Host-directed drug targeting of factors hijacked by pathogens. Sci Signal 1:re8. https://doi.org/10.1126/scisignal.129re8

    Article  PubMed  Google Scholar 

  8. Mayer-Barber KD et al (2014) Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature 511:99–103. https://doi.org/10.1038/nature13489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tobin DM et al (2012) Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148:434–446. https://doi.org/10.1016/j.cell.2011.12.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ejim L et al (2011) Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol 7:348–350. https://doi.org/10.1038/nchembio.559

    Article  CAS  PubMed  Google Scholar 

  11. Wallis RS, Hafner R (2015) Advancing host-directed therapy for tuberculosis. Nat Rev Immunol 15:255–263. https://doi.org/10.1038/nri3813

    Article  CAS  PubMed  Google Scholar 

  12. Singhal A et al (2014) Metformin as adjunct antituberculosis therapy. Sci Transl Med 6:263ra159, doi:6/263/263ra159 [pii]. https://doi.org/10.1126/scitranslmed.3009885

    Article  CAS  Google Scholar 

  13. Hundal RS et al (2000) Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49:2063–2069. https://doi.org/10.2337/diabetes.49.12.2063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Leow MK et al (2014) Latent tuberculosis in patients with diabetes mellitus: prevalence, progression and public health implications. Exp Clin Endocrinol Diabetes 122:528–532. https://doi.org/10.1055/s-0034-1377044

    Article  CAS  PubMed  Google Scholar 

  15. Marupuru S et al (2017) Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Braz J Infect Dis 21:312–316, S1413-8670(16)30495-0 [pii]. https://doi.org/10.1016/j.bjid.2017.01.001

    Article  PubMed  Google Scholar 

  16. Pan S-W et al (2018) The risk of TB in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment. Chest 153:1347

    Article  Google Scholar 

  17. Degner NR, Wang JY, Golub JE, Karakousis PC (2018) Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment. Clin Infect Dis 66:198–205, 4161913 [pii]. https://doi.org/10.1093/cid/cix819

    Article  CAS  PubMed  Google Scholar 

  18. Lin SY et al (2018) Metformin is associated with a lower risk of active tuberculosis in patients with type 2 diabetes. Respirology 23:1063–1073. https://doi.org/10.1111/resp.13338

    Article  PubMed  Google Scholar 

  19. Lee YJ et al (2018) The effect of metformin on culture conversion in tuberculosis patients with diabetes mellitus. Korean J Intern Med. kjim.2017.249 [pii]. https://doi.org/10.3904/kjim.2017.249

  20. Lee MC et al (2018) Metformin use is associated with a low risk of tuberculosis among newly diagnosed diabetes mellitus patients with normal renal function: a nationwide cohort study with validated diagnostic criteria. PLoS One 13:e0205807. https://doi.org/10.1371/journal.pone.0205807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ma Y et al (2018) Metformin reduces the relapse rate of tuberculosis patients with diabetes mellitus: experiences from 3-year follow-up. Eur J Clin Microbiol Infect Dis. https://doi.org/10.1007/s10096-018-3242-6. [pii]

  22. Santos A et al (2017) The effect of metformin on smear and culture conversion of diabetic patients with tuberculosis. Am J Respir Crit Care Med 195:A2110

    Google Scholar 

  23. Magee MJ, Salindri AD, Kornfeld H, Singhal A (2019) Reduced prevalence of latent tuberculosis infection in diabetes patients using metformin and statins. Eur Respir J 53. https://doi.org/10.1183/13993003.01695-2018

  24. Tseng CH (2018) Metformin decreases risk of tuberculosis infection in Type 2 diabetes patients. J Clin Med 7. https://doi.org/10.3390/jcm7090264

  25. Schulten HJ (2018) Pleiotropic effects of metformin on cancer. Int J Mol Sci 19. https://doi.org/10.3390/ijms19102850

  26. Forouzandeh F et al (2014) Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis. J Am Heart Assoc 3:e001202. https://doi.org/10.1161/JAHA.114.001202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Viollet B, Andreelli F (2011) AMP-activated protein kinase and metabolic control. Handb Exp Pharmacol:303–330. https://doi.org/10.1007/978-3-642-17214-4_13

  28. Zhou G et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174. https://doi.org/10.1172/JCI13505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Turban S et al (2012) Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells. J Biol Chem 287:20088–20099. https://doi.org/10.1074/jbc.M111.330746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Viollet B et al (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122:253–270. https://doi.org/10.1042/CS20110386

    Article  CAS  Google Scholar 

  31. Di Fusco D et al (2018) Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation. Clin Sci (Lond) 132:1155–1168. https://doi.org/10.1042/CS20180167

    Article  CAS  Google Scholar 

  32. Kajiwara C et al (2018) Metformin mediates protection against legionella pneumonia through activation of AMPK and mitochondrial reactive oxygen species. J Immunol 200:623–631. https://doi.org/10.4049/jimmunol.1700474

    Article  CAS  PubMed  Google Scholar 

  33. Singhal A et al (2014) Metformin as adjunct antituberculosis therapy. Sci Transl Med 6:263ra159. https://doi.org/10.1126/scitranslmed.3009885

    Article  CAS  PubMed  Google Scholar 

  34. Lachmandas E et al (2019) Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects. J Infect Dis 220:139–150. https://doi.org/10.1093/infdis/jiz064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jo EK, Silwal P, Yuk JM (2019) AMPK-targeted effector networks in mycobacterial infection. Front Microbiol 10:520. https://doi.org/10.3389/fmicb.2019.00520

    Article  PubMed  PubMed Central  Google Scholar 

  36. El-Mir MY et al (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228. https://doi.org/10.1074/jbc.275.1.223

    Article  CAS  Google Scholar 

  37. Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348 Pt 3:607–614

    Article  CAS  Google Scholar 

  38. He L et al (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137:635–646. https://doi.org/10.1016/j.cell.2009.03.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fullerton MD et al (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 19:1649–1654. https://doi.org/10.1038/nm.3372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin. Diabetologia 60:1577–1585. https://doi.org/10.1007/s00125-017-4342-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wheaton WW et al (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. elife 3:e02242. https://doi.org/10.7554/eLife.02242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bridges HR, Jones AJ, Pollak MN, Hirst J (2014) Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 462:475–487. https://doi.org/10.1042/BJ20140620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Madiraju AK et al (2018) Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24:1384–1394. https://doi.org/10.1038/s41591-018-0125-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Madiraju AK et al (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–546. https://doi.org/10.1038/nature13270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Foretz M, Guigas B, Viollet B (2019) Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 15:569–589. https://doi.org/10.1038/s41574-019-0242-2

    Article  CAS  PubMed  Google Scholar 

  46. Langston PK et al (2019) Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses. Nat Immunol 20:1186–1195. https://doi.org/10.1038/s41590-019-0453-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gleeson LE et al (2016) Cutting edge: Mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication. J Immunol (Baltimore, Md : 1950) 196:2444–2449. https://doi.org/10.4049/jimmunol.1501612

    Article  CAS  Google Scholar 

  48. Shi L et al (2015) Infection with Mycobacterium tuberculosis induces the Warburg effect in mouse lungs. Sci Rep 5:18176. https://doi.org/10.1038/srep18176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schwartz L, Seyfried T, Alfarouk KO, Da Veiga Moreira J, Fais S (2017) Out of Warburg effect: an effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin Cancer Biol 43:134–138. https://doi.org/10.1016/j.semcancer.2017.01.005

    Article  CAS  PubMed  Google Scholar 

  50. O’Sullivan D, Sanin DE, Pearce EJ, Pearce EL (2019) Metabolic interventions in the immune response to cancer. Nat Rev Immunol 19:324–335. https://doi.org/10.1038/s41577-019-0140-9

    Article  CAS  PubMed  Google Scholar 

  51. Russell DG, Huang L, VanderVen BC (2019) Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol 19:291–304. https://doi.org/10.1038/s41577-019-0124-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pierotti MA et al (2013) Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 32:1475–1487. https://doi.org/10.1038/onc.2012.181

    Article  CAS  PubMed  Google Scholar 

  53. Thakur S et al (2018) Metformin targets mitochondrial glycerophosphate dehydrogenase to control rate of oxidative phosphorylation and growth of thyroid cancer in vitro and in vivo. Clin Cancer Res 24:4030–4043. https://doi.org/10.1158/1078-0432.CCR-17-3167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hunter RW et al (2018) Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat Med 24:1395–1406. https://doi.org/10.1038/s41591-018-0159-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jung SB et al (2018) Reduced oxidative capacity in macrophages results in systemic insulin resistance. Nat Commun 9:1551. https://doi.org/10.1038/s41467-018-03998-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Luan HH et al (2019) GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell 178:1231–1244 e1211. https://doi.org/10.1016/j.cell.2019.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Coll AP et al (2020) GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578:444–448. https://doi.org/10.1038/s41586-019-1911-y

    Article  CAS  PubMed  Google Scholar 

  58. Dutta NK, Pinn ML, Karakousis PC (2017) Metformin adjunctive therapy does not improve the sterilizing activity of the first-line antitubercular regimen in mice. Antimicrob Agents Chemother 61. https://doi.org/10.1128/AAC.00652-17

  59. Russell SL et al (2019) Compromised metabolic reprogramming is an early indicator of CD8(+) T Cell dysfunction during chronic Mycobacterium tuberculosis infection. Cell Rep 29:3564–3579.e3565. https://doi.org/10.1016/j.celrep.2019.11.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lee MC, Lee CH, Lee MR, Wang JY, Chen SM (2019) Impact of metformin use among tuberculosis close contacts with diabetes mellitus in a nationwide cohort study. BMC Infect Dis 19:936. https://doi.org/10.1186/s12879-019-4577-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kumar NP et al (2018) Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment. BMC Infect Dis 18:345. https://doi.org/10.1186/s12879-018-3246-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ravimohan S, Kornfeld H, Weissman D, Bisson GP (2018) Tuberculosis and lung damage: from epidemiology to pathophysiology. Eur Respir Rev 27, 27/147/170077 [pii]. https://doi.org/10.1183/16000617.0077-2017

  63. Padmapriyadarsini C et al (2019) Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial. BMJ Open 9:e024363. https://doi.org/10.1136/bmjopen-2018-024363

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sacks LV, Pendle S (1998) Factors related to in-hospital deaths in patients with tuberculosis. Arch Intern Med 158:1916–1922

    Article  CAS  Google Scholar 

  65. Elkington PT, Ugarte-Gil CA, Friedland JS (2011) Matrix metalloproteinases in tuberculosis. Eur Respir J 38:456–464, 09031936.00015411 [pii]. https://doi.org/10.1183/09031936.00015411

    Article  CAS  PubMed  Google Scholar 

  66. Ravimohan S et al (2016) Matrix metalloproteinases in tuberculosis-immune reconstitution inflammatory syndrome and impaired lung function among advanced HIV/TB co-infected patients initiating antiretroviral therapy. EBioMedicine 3:100–107. https://doi.org/10.1016/j.ebiom.2015.11.040. [doi];S2352-3964(15)30223-1 [pii]

    Article  PubMed  Google Scholar 

  67. Rangarajan S et al (2018) Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 24:1121–1127. https://doi.org/10.1038/s41591-018-0087-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yin W, Han J, Zhang Z, Han Z, Wang S (2018) Aloperine protects mice against bleomycin-induced pulmonary fibrosis by attenuating fibroblast proliferation and differentiation. Sci Rep 8:6265. https://doi.org/10.1038/s41598-018-24565-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Azmoonfar R et al (2018) Metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression. Adv Pharma Bullet 8:697–704. https://doi.org/10.15171/apb.2018.078

    Article  CAS  Google Scholar 

  70. Gupte AN et al (2019) Assessment of lung function in successfully treated tuberculosis reveals high burden of ventilatory defects and COPD. PLoS One 14:e0217289. https://doi.org/10.1371/journal.pone.0217289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ravimohan S et al (2019) A common NLRC4 gene variant associates with inflammation and pulmonary function in human immunodeficiency virus and tuberculosis. Clin Infect Dis. https://doi.org/10.1093/cid/ciz898

  72. Malik F et al (2018) Is metformin poised for a second career as an antimicrobial? Diabetes Metab Res Rev 34:e2975. https://doi.org/10.1002/dmrr.2975

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This research was supported by SIgN A*STAR and NIH Grant (#R01HL081149 to HK, #R01HL152078 to AS and HK).

Author information

Authors and Affiliations

  1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Amit Singhal

  2. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Amit Singhal

  3. Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, India

    Amit Singhal

  4. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Hardy Kornfeld

Authors
  1. Amit Singhal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hardy Kornfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Amit Singhal or Hardy Kornfeld .

Editor information

Editors and Affiliations

  1. Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    Petros C. Karakousis

  2. Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, Rockville, MD, USA

    Richard Hafner

  3. Public Health Research Institute New Jersey Medical School Rutgers Biomedical and Health Sciences, Rutgers-The State University of New Jersey, Newark, NJ, USA

    Maria Laura Gennaro

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Singhal, A., Kornfeld, H. (2021). Metformin: A Leading HDT Candidate for TB. In: Karakousis, P.C., Hafner, R., Gennaro, M.L. (eds) Advances in Host-Directed Therapies Against Tuberculosis . Springer, Cham. https://doi.org/10.1007/978-3-030-56905-1_7

Download citation

Publish with us

Policies and ethics

Search

Navigation