host directing therapy for TB

1. HOST DIRECTED THERAPIES
FOR FIGHT AGAINST T.B.
Presented by - Monika Kumar Shirke.
Seminar Guide - Dr. Rakesh Somani .

2. CONTENTS
Introduction
Global Status of TB
History of TB
What is T.B.?
Common Symptoms of TB
Tuberculosis Affects Many Parts of the Body
Pathogenesis of T.B.
Current Anti-TB drugs

3. New Anti-TB drugs
What is HDT ?
Objectives of HDT
How HDT Fight against TB?
Classes of HDT
Development of HDT for T.B
Strategies of development of TB HDT
Advantages of HDT by Anti-T.B. drugs/repurposed drug
References

4. INTRODUCTION

5. Global Status of TB
Distribution –worldwide
WHO estimates that about 9.2 million new cases of TB occurred in 2006.
India is the first rank in incidence.
1/5 th of global burden of TB
1.8 million persons develop TB of which 0.8 million are new smear positive(highly
infectious)
0.37 million people die every year.
World TB day on 24 march.

6. History of TB
Tuberculosis is an Ancient Disease.
Spinal Tuberculosis in Egyptian Mummies
History dates to 1550-1080 BC identified by PCR

7. Robert Koch
Discoverer of
Mycobacterium Tuberculosis

8. What is T.B.?
Tuberculosis or TB is a disease caused by Mycobacterium
tuberculosis, Mycobacterium bovis, Mycobacterium africanum,
Mycobacterium microtti & Mycobacterium canetti.
Mycobacterium tuberculosis is highly aerobic acid fast bacilli, slow
generation time15-20 hrs.,unable to digested by
microphages.
Spread through air by inhalation of airborne bacteria
from infected.

9. Common Symptoms of TB
Cough(2-3 weeks or more)
Coughing up blood
Chest pains
Fever
Night sweats
Feeling weak & tired
Loss of appetite

10. Tuberculosis Affects Many Parts of the Body

11. Pathogenesis of T.B.

12. Current Anti-TB drugs
Classification Drug Name MOA
1 st line
drugs
Ethambutol Inhibits mycobacterial arabinosyl transferases. Arabinosyl transferases are
involved in the polymerization reaction of arabinoglycan ,as essential
component of the mycobacterial cell wall.
Isoniazid It blocks mycolic acid synthesis & kills the cell.
Rifampicin It binds to β –subunit of bacterial DNA dependent RNA polymerase &
inhibit RNA synthesis.
Pyrazinamide Pyrazinamide converts into pyrazinoic acid (POA).POA decreases the pH
below that retards the growth of Mtb. & inhibiting the fatty acid synthesis.
Streptomycin Irreversibly inhibits bacterial protein synthesis.

13. Salicylates-Para-amino benzoic
acid(PABA)
To inhibit folic acid biosynthesis and uptake of iron.
Ethionamide Similar to isoniazide.
Cycloserine It inhibits the incarporation of D-alanine into peptidoglycan
pentapeptide by inhibiting alanine racemase. Inhibits mycobacterial
cell wall synthesis.
Thiacetazone Bacteriostatic inhibits cyclopropanaton of cell wall mycolic acid.
Quinolones-ciprofloxacin Inhibits bacterial DNA synthesis by inhibiting bacterial
topoisomerase
Macrolides-Azithromycin Bind to 50s ribosomal subunits & blocks dissociation of peptidyl t-
RNA from ribosomes causing RNA –dependent protein synthesis.
Amino glycosides-Kanamycin Bacteriocidal & believed to inhibits protein synthesis by binding to
30s ribosomes subunit
Classification
2 nd line
drugs

16. New Anti-TB drugs
Drug Name MOA
Rifapentine Inhibits DNA -dependent RNA polymerase in susceptible strains of M.tb
Clofazimine Release of reactive oxygen species(ROS) and cell membrane distruption
Bedaquilline Inhibition of mitochondrial ATP synthase
Delamanid Mycolic acid biosynthesis inhibition
Pretomanid Inhibition of cell wall of mycolic acid biosynthesis
Sutezolide Protein synthesis inhibitor .

18. Pretomanid
Delamanid
Bedaquiline
Sutezolid

19. What is HDT ?
HDT-host directed therapies are a relatively new & promising approach to
treatment of tuberculosis.

20. What is HDT ?
Therapy that targets host factor which are usually part of immune system in
order to :
 Potentiate human antimicobacterial effector mechanism.
Modulate innate and adaptive immune response.
Limit inflammation
Reduce tissue damage (Enzyme activity)
Limit long term effects of tissue destruction and fibrosis

21. Objectives of HDT
Activity against antibiotic resistant Mtb strains
Possibly synergy with antibiotics
Possibly activity against non-replicating Mtb
Reduced likehood of resistance
Inhibit host factors used for Mtb pathogen
Augment innate & adaptive immune response to Mtb
Inhibit deterious immune response to Mtb
Induce novel immune response to Mtb
Inhibit bacterial functions & facilate host response

22. Strategies of development of TB HDT

23. Modulation of
Cytokine response
Inhibition of immune
check point
Cellular therapy
Immunomodulatory
antigen from pathogen
Targeting
Pathogen Factor
Current anti-TB drugs Strategies of development of TB HDT
Repurposed drugs

24. Repurposed drugs

25. Activates adenosine monophosphate-activated protein kinases.
Metformin inhibits MTB growth by inducing mitochondrial ROS production.
It reduces the TB-mediated tissue pathology.
Enhances IFN-γ-secreting CD8+ and CD4+ T-cell
Imatinib is a small-molecule kinase inhibitor that blocks tyrosine kinase enzymes.
The therapeutic administration of imatinib promotes the acidification and maturation of MTB-
infected macrophage phagosomes, reducing the number of colony-forming units (CFUs) in MTB-
infected mice. Inhibit drug-resistant mycobacterial strains.
Imatinib strengthens host defenses by increasing neutrophil and monocyte numbers through
myeloproliferation.
 Ibuprofen is a non-steroidal anti-inflammatory drug normally used as a painkiller and an
antipyretic.
This inhibitor of cyclooxygenase inhibits prostaglandin E2 production and enhances tumor
necrosis factor (TNF) 1 production in macrophages.
 It reduces lung tuberculosis.
Ibuprofen
Imatinib
Metformin

26. Modulation of Cytokine response

27. IL-2
GM-
CSF
IFN-γ
IL-2 induces the expansion of T cells.
However, recent studies have shown that IL-2 promotes CD4+CD25+ regulatory T-cell expansion, which
suppresses the T-cell response .
Some clinical trials checking the effectiveness of IL-2 against TB have been reported .
 IFN-γ plays a major role in the host defense against MTB.
IFN-γ, as a prototypical product of Th1 cells, promotes the secretion of Th1 cytokines (such as IL-12) and
inhibits Th2 cytokines (such as IL-4).
 In addition, IFN-γ up regulates class I and II antigen-presenting cells and increases the antimicrobial
activity of macrophages.
Mutations in the IFN-γ receptor gene result in high susceptibility to mycobacterial infections .
Granulocyte macrophage colony-stimulating factor (GM-CSF) increases the number of macrophages,
leading to an enhanced inflammatory response.
GM-CSF also shows antimycobacterial activity in human macrophages .
GM-CSF plays critical immunomodulatory roles in the host defense against pulmonary TB .

28. Inhibition of immune check point

29. Anti-CTLA-4
Anti-LAG3
Anti-PD1
CTLA-4 (Cytotoxic T Lymphocyte Associated Protein 4)Ipilimumab –monoclonal antibody
that works to activate the immune system by targeting.
Lymphocyte –activation gene 3 (LAG3) used in cancer treatment. CTLA-4.Suppress immune
response by direct effect on T cell
Programmed cell death 1 (PD-1) is a protein on the surface of active T cells. When
programmed death-ligand 1 (PD-L1) and PD-L2 .Advantage of targeting PD1 is that it can
restore immune function in tumor microenvironment. Nivolumab/pembrolizumab are PD-1
inhibitors currently used to treat melanomas and other cancers

30. Cellular therapy

31. Bone marrow-derived
mesenchymal stromal cells
Antigen-specific T cells
Targeted killing of MTB-
infected host cells
Reduction of inflammation and
enhancement tissue regeneration

32. Immunomodulatory antigen from pathogen

33. GRA7 antigen driven
intra cellular parasite T.
gondii.
GRA7 controlled the innate immune response by
interacting with host cell proteins.
GRA7 is essential for the interaction between
apoptosis-associated speck-like protein containing a
carboxyl-terminal CARD and phospholipase D1.
These interactions induced antibacterial activity against
TB.

34. Vitamin D3
Vitamin D3 is a dietary supplement that activates the innate immune
response.
Low vitamin D3 levels are involved in the development of active TB.
Vitamin D3 has an important role in converting 2,5(OH)D into 1,25-
(OH)2D3, which is its active form.
 This active form induces the production of cathelicidin, which is an
antimicrobial peptide.

36. Classes of HDT

37. Development of HDT for T.B.
Category Name Currently approved indication(s) Host target
Repurposed
drug
Imatinib Leukemia and gastrointestinal stromal
tumors
Tyrosine kinase
Verapamil High blood pressure, chest pain and
supraventricular tachycardia.
Voltage-dependent calcium
channels
Metformin Diabetes AMP-activated protein
kinase activator
Ibuprofen Pain and fever relief Cyclooxygenase inhibitor

38. Cytokine
therapy
IL-2 Renal cancer and melanoma Cytokine modulation
GM-CSF Acute Myelogenous Leukemia, after
bone marrow transplantation
Cytokine modulation
IFN-γ Chronic granulomatous disease Cytokine modulation
Monoclonal
antibody
Adalimumb (Anti-TNFα) Rheumatoid arthritis Cytokine neutralization
Tocilizumab (Anti-IL6R) Juvenile arthritis, Castleman's disease Cytokine neutralization
Bevacizumv (Anti-VEGF) Various cancer types Angiogenesis inhibitor

39. Monoclonal
antibody
Nivolumab
/pembrolizumab (Anti-
PD-1)
Melanoma, various other cancers Immune check point inhibitor
Anti-LAG3 Various cancers Immune check point inhibitor
Ipilimumab (Anti-CTLA-
4)
Melanoma, various other cancers Immune check point inhibitor
Vitamin Vitamin D3 Dietary supplement Innate immune response
activator
Cellular
therapy
Bone marrow-derived
mesenchymal stromal
cells
Various inflammatory indications Reduction of inflammation and
enhancement tissue regeneration
Antigen-specific T cells Cancer and viral infections Targeted killing of MTB- infected
host cells

40. Advantages of HDT by Anti-T.B. drugs/repurposed
drug
Well established safety profiles.
Shorter therapy duration.
Lower risk of relapse or re-infection.
Effective against drug -resistant cases.
Can be adopted to any chronic infections.

41. REFERENCES

42. REFERENCES
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44. THANK YOU