Treatments and Disease Management

Vitamin D

Before any formal treatments such as antibiotics and chemotherapy were developed, vitamin D was used to treat tuberculosis (Martineau et al. 2007).  Although the use of vitamin D to treat tuberculosis became uncommon with the development of antimycobacterial treatments, it has since come back into rotation due to its ability to enhance immune response (Martineau et al. 2007).

The active form of vitamin D, 1,25-dihydroxy-vitamin D, also called calcitriol, is what regulates the response to the bacteria infection (Martineau et al. 2007). To produce calcitriol, 1α-hydroxylase adds a hydroxyl group to 25-hydroxy-vitamin D (Martineau et al. 2007).

In the active form of the disease, Mycobacterium tuberculosis will be confined within macrophages, which become surrounded by T cells (Martineau et al. 2007). These specific macrophages that respond the infection contain a gene that encodes 1α-hydroxylase, and the T cells secrete interferon gamma (IFNg), which increases the upregulation of 1α-hydroxylase and inhibits the production of an enzyme that inactivates calcitriol (Martineau et al. 2007).

Macrophage and T Cells Upregulate Calcitriol. Source: http://www.sciencedirect.com/science/article/pii/S0960076006004304
Macrophage and T Cells Upregulate Calcitriol. Source: http://www.sciencedirect.com/science/article/pii/S0960076006004304

Calcitriol gives rise to respiratory bursts and increases phagolysosome fusion in macrophages containing M. tuberculosis (Martineau et al. 2007). These bolster the immune response by damaging, and ultimately killing, the bacteria (Martineau et al. 2007).

Antimycobacterial Latent Tuberculosis Treatments

Although patients with latent tuberculosis are not contagious, and do not exhibit any signs or symptoms of the disease, they still must undergo treatment to prevent the development of active tuberculosis (CDC Basic TB Facts). The medications used for treatment include isoniazid, rifampin, and rifapentine (CDC Basic TB Facts). These medications can be used individually, or in combination with each other (CDC Basic TB Facts). However, the length of treatment varies depending on the medication, and treatment can last anywhere between 3 and 9 months (Zumla et al. 2015).

Antimycobacterial Active Tuberculosis Treatments

Treatments for active tuberculosis can include the same medications used to treat latent tuberculosis (CDC Basic TB Facts). However, these medications can be supplemented with small molecules that enhance host immune response. One of these molecules, R207910, also known as bedaquiline, has been proven to be one of the most effective antimycobacterial supplements (Andries et al. 2005). It was determined that the atpE gene is the target for bedaquiline, and since this target is so specific, bedaquiline will not interfere with other tuberculosis treatments (Andries et al. 2005). Bedaquiline works by inhibiting ATP synthase, thus leading to a decrease in the amount of ATP available for the bacterium and a disruption in pH homeostasis necessary for survival (Adries et al. 2005).

Absolute Configuration of Bedaquiline. Source: http://science.sciencemag.org/content/307/5707/223.full
Absolute Configuration of Bedaquiline. Source: http://science.sciencemag.org/content/307/5707/223.full

 

 

8 Replies to “Treatments and Disease Management”

  1. Hi – what a nice review on TB treatment! I am very curious about bedaquiline. Tuberculosis has a long history with antibiotic treatment which has more recently been plagued with antibiotic resistance in particular strains. I was wondering if bedaquiline has been specifically studied in these resistant strains or if other small molecules are being looked at to combat this resistance.

    Thanks and good work!

    Anne

    1. Thanks for your feedback Anne! I really appreciate it! Bedaquiline has actually been proven to inhibit drug-resistant Mycobacterium tuberculosis in vitro. However, I could not find experiments wherein it was able to inhibit it in vivo, but it was able to inhibit Mycobacterium leprae, a bacterium very similar it M. tuberculosis, in vivo. Clinical trials using bedaquiline were eventually approved by the FDA, however there is a chance for increased mortality when taking this drug even though it can inhibit M. tuberculosis due to the possibility of inducing an acquired heart condition that leads to sudden death. I hope that sufficiently answers your question! Thanks again for your feedback!

  2. Great work Nikki! You provide very clear and informative pages explaining the various aspects of the disease. I am curious about the antimycobacterial latent tuberculosis treatments of isoniazid, rifampin, and rifapentine. Are the mechanistic details of how these drug treatments act explained in any studies or literature? Additionally, do all of these three treatments act in the same way to produce similar reults? I am curious to see how the effects of these treatments result in controlling the bacterium that is the causative agent of this disease.

    1. Thanks Tyler! The mechanism of action for isoniazid is different from rifampin and rifapentine. Isoniazid inhibits the synthesis of mycolic acids, which is necessary for the mycobacterial cell wall. Mycolic acids give the cell wall a thick, waxy layer, which makes it difficult for the immune response, as well as other drugs, to act on the bacterium. Rifampin and rifpentine both inhibit DNA-dependent RNA polymerase, so they essentially inhibit the bacterium from replicating.

      Isoniazid isn’t active until it interacts with the bacterial catalase-peroxidase enzyme KatG, which forms an isonicotinic acyl-NADH complex, which binds to a reductase called InhA. This now blocks a substrate necessary for the fatty acid synthesis. Both rifampin and rifpentine bind to prokaryote RNA polymerase at the next to its active site, which inhibits it. I hope that sufficiently answers your questions!

  3. Great Work. I thought your explanations on how tuberculosis spreads and the immune response to tuberculosis, to be thorough. Why isn’t bedaquiline used on latent tuberculosis to enhance host immune response during treatments? Its seems that I should be just as effective in the active form as it would be helping to treat tuberculosis in its latent form.

    1. Thanks Zach! Due to the fact that one of the side effects of bedaquiline is an acquired heart condition that can lead to sudden death, there is a high risk in using this drug. Since latent TB does not result in any harmful symptoms, it would be a greater risk to take this drug as opposed to letting the TB remain dormant. If it is in its active form though, the harmful symptoms will be present, so this risk will outweigh the cost in the case of active TB. I hope this answers your question!

  4. Hello Nicole!
    As someone who had a family member diagnosed and treated for Tuberculosis, this topic hits home for me. I really enjoyed reading through your Treatment page and it was mentioned that researchers should investigate drug therapies which target not only MTB’s cysteine biosynthesis. How far along do you feel research into this area is and which alternative inhibitors show the most promise as drug therapies?
    Great work, Nicole! I really enjoyed reading about your disease!
    Tyler Florio

    1. Thanks Tyler! I’m so glad you enjoyed this page! So far, a lot of the research in this area has been investigating the different cysteine biosynthetic pathways and finding targets for drugs. However, there has yet to be a drug developed in order to inhibit these pathways. Since this discovery is relatively recent, I think it will be a few more years before we see an actual drug developed to be tested! I hope this sufficiently answered your questions!

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