The New Strategies for Improving The Treatment of Tuberculosis

Initial protection against TB is accomplished through the BCG vaccine which is administered at birth. This vaccine should last for up to 15 years. Even with the availability of this vaccine, tuberculosis remains as devastating a disease as ever. While it only takes a week or two of monotherapy to cure most bacterial infections, to successfully treat tuberculosis, it takes a minimum of 6 months using a wide range of antibiotics to combat uncomplicated drug sensitive TB, with a cure rate of 90%.

Since 1994, the same four drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) have been used as the first step in treatment of TB. However, factors including the extended treatment time and noncompliance of patients has led to the emergence of drug resistant TB strains such as XDR-TB which, at the very least, are resistant to isoniazid and rifampicin. This multi-drug resistant strain requires at least 20 months of treatment using drugs that are toxic and have a reduced cure rate of 60%-75%. In the 1990’s the research into the development of anti-TB drugs came to a halt. With the first line of drugs showing the ability to cure TB and the fact that most new cases are found outside the developed world, has led to a drop in the overall incentive for investment in the development of new anti-TB drugs.

The extensive antimicrobial resistance in TB has drawn attention back to the once neglected strategies for improving the treatment of TB.

One of the reasons Mycobacteria have a strangely high antimicrobial resistance may be due to the unique complexity if its cell wall. It contains a complex network of macromolecules including mycolic acid (MAgP complex) that allows Mycobacterium tuberculosis to be impervious to techniques such as gram staining. this, along with arabinogalactan, peptidoglycan and various other proteins and polysaccharides combine to form the main scaffold of the mycobacterial cell wall. Forming an incredibly high barrier to cross for antimicrobial agents.

Antimicrobial peptides (AMPs) represent a new treatment strategy against Tuberculosis that can overcome the protection of the cell wall. One of the main mechanisms of AMP interactions is their ability to either completely disrupt the cell membrane or create transient pores. The first step of the interaction between AMPs and the bacterial cell is the mediation of their positive charge to bind to the negatively charged prokaryotic cell surface. The binding between the cationic residues of the AMP and the anionic cell surface of the cell encourages the membrane to become more permeable. This makes it possible for many AMPs to apply killing mechanism through the disruption of the cell membrane. Despite the direct killing mechanism wielded by the antimicrobial peptides, aswell as their immunomodulatory properties, AMPs are still facing major challenges when it comes to joining the pharmaceutical industry. Some major drawbacks of the use of AMPs in strategies against TB incluse high cost of synthesis, low stability in human biological fluids and the potential of tumorigenesis and angiogenesis as side effects when administered at high concentrations. However, the long list of advantages to this kind of therapy including the multi-functionality, rapid direct killing mechanism and synergy with current antibiotics show potential for a promising new treatment for tuberculosis.

TB bio markers have the potentil to be extremely useful tools to use to measure infection status and predict outcome of infection, vaccination or therapy. Pulmonary TB requires a Mtb-positive sputum for the diagnostic assays which, many active TB patients, including, HIV-coinfected individuals, diabetes patients and children do not possess. New TB diagnostics need to be developed that can work on non-sputum-based tests within countries with limited resource as well as be able to perform at low cost in endemic settings with limited facilities using non-sputum samples such as blood or urine. Consequently, the search for biomarkers that can be used in these tests is crucial to combating TB.

Mycobacterium tuberculosis products can be detected from bodily fluids such as blood, sputum and urine. Urine and sputum sample are often used in diagnostic assay for infectious diseases as sample collection is both non-invasive and produces a large volume of sample. Since urine is a filtrate of the blood it holds the potential to be considered a representative of all the organs in the body where the infection may be.

The goal of TB treatment using biomarkers if to clear the bacterium and at the same time prevent relapse. Although treatment initially targets the pathogen, host biomarkers can be used to both measure and predict the patient’s response to the treatment administered. TB-BM are used to show whether or not a patient has become immune (Correlate of Protection or CoP) after receiving vaccination, has acquired the disease(Correlate of TB Disease or CoD), is has developed an increased risk of active TB infection (Correlate of Risk or CoR). With these biomarkers, the outcome of treatment course can be predicted and monitored. However, the implementation of this application requires additional research.

Along side the creation of new techniques for combating TB, there have been new drug discovies that may also aid in the fight against TB. One such drug is known as Bedaquiline. Bedaquiline has been seen to block ATPase synthesis and while it did appear to work well in bacterial clearance, the group being tested ended up with more deaths than the comparative study. Delamanid and Pretomanid have also shown promise in being effective against TB, although, would appear to require pyrazinamide to present in order to work at maximum effictiency.