NOVEL ANTI-TUBERCULOSIS DRUGS

Introduction:

Tuberculosis is a highly contagious disease, caused by Mycobacterium tuberculosis, which belongs to the genus MYCOBACTERIUM (3). It is an air-borne infection. Mycobacterium tuberculosis enters the host through nostrils and affects lungs, but can also affects the central nervous system, lymphatic system, and circulatory system (2). Tuberculosis is known as PHTHISIS or CONSUMPTION, which means the deadliest disease to human (4). Mycobacterium tuberculosis can cause two types of infections:

1.    Active contagious tuberculosis

2.    Latent tuberculosis

Active contagious tuberculosis is diagnosed by chest X-rays, microscopic examination of sputum (Acid fast bacilli or AFB staining), and microbiological culture of sputum. Whereas latent tuberculosis (Mycobacterium tuberculosis present in the body remains inactive and symptoms do not appear) is diagnosed by Mantoux tuberculin skin test and interferon gamma release assays (IGRAs) of the blood (2).

Tuberculosis is a serious health problem in all over the world, Morbidity and mortality rate of tuberculosis remains high globally, the incidence rate of tuberculosis rises every year (1). The infectious dose of Mycobacterium tuberculosis is very low that is 10 mycobacterial cells (2). The transmission of tuberculosis is high within tuberculosis-affected households as well as outside household (such as: in schools, working places, hospitals, prisons, crowd etc.) (1). Individuals who have any underlying diseases such as, AIDs, Diabetes mellitus, malnutrition, cigarette smoke, silicosis, alcoholism etc. are more susceptible to Tuberculosis (2).

Treatment Of Tuberculosis:

Anti-mycobacterial drugs are the effective agents against mycobacterium tuberculosis. Single anti-mycobacterial drug is used for the treatment of latent tuberculosis, whereas combination of different drugs is used for the treatment of active tuberculosis to reduce the development of multi-drug resistant bacteria (2).

There are two lines of drugs available for the treatment of tuberculosis.

1.    First line anti-tuberculosis drugs

2.    Second line anti-tuberculosis drug

 

1.    First Line Anti-Tuberculosis Drugs:

Isoniazid (INH), Rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) are used as first line anti-tuberculosis drugs for two months, followed by continuation of isoniazid and rifampicin for four months. Streptomycin is also a bactericidal antibiotic, but it no longer used as a first line drug because mycobacterium tuberculosis shows resistant against it (2).

 

2.    Second Line Anti-Tuberculosis Drugs:

Amikacin (AKA), kanamycin (KM), para-amino salicylic acid (PSA), cycloserine (CYS), ethionamide (ETA), capreomycin (CPR), and ciprofloxacin are used as second line anti-tuberculosis drugs (2).

 

Mycobacterium Tuberculosis Resistant To Drug:

Mycobacterium tuberculosis becomes resistant to drugs during the treatment course because of the poor management of chemotherapy and incorrect or inappropriate treatment as a result treatment becomes more complex, increasing its duration and side effects. Multi-drug resistant tuberculosis (MDR-TB) shows resistance against isoniazid and rifampicin, while extensive drug resistant tuberculosis (XDR-TB) shows resistance to at least three out of six second line anti-tuberculosis drugs (amikacin or kanamycin, ethionamide, cycloserine, capreomycin, para-amino salicylic acid, fluoroquinolones) (2).

 

Mechanism Of Drug Resistance In Mycobacterium Tuberculosis:

There are certain mechanisms in mycobacterium tuberculosis which can alter the binding affinity of drugs, reduced the efficiency of drugs, and become resistant to anti-tuberculosis drugs. As shown in table:1 and table:2 (5)

Table:1  First Line Anti-Tuberculosis Drugs:

Drug	Mechanism Of Action	Gene(S) Involved In Resistance	Mechanism Of Resistance
Isoniazid	Inhibition of mycolic acid biosynthesis	KatG (catalase-peroxidase)	Mutation in KatG results in failure to generate an active intermediate isoniazid
		inhA (enoyl-acyl carrier protein reductase)	Overexpression of inhA allows continuation of mycolic acid synthesis
		ahpC (alkylhydroxy-peroxide reductase)	ahpC mutation just serve as a marker for isoniazid resistance
Rifampicin	Inhibition of transcription	rpoB (β-subunits of RNA polymerase)	Mutation in rpoB prevent interaction with rifampicin
Pyrazinamide	Depletion of membrane energy by inhibition of membrane transport	pncA (pyrazimidase-nicotinamidase)	Mutation in pncA results loss of pyrazinamidase activity as a result decrease in conversion of pyrazinamide to pyrazinoic acid, the putative active moiety
Ethambutol	Inhibition of arabinoglactan and lipoarabinomannan biosynthesis	embB (arabinosyl transferase)	Mutation in embB allows continuation of arabinoglactan biosynthesis
Streptomycin	Inhibition of protein synthesis	rpsL (ribosomal protein S12)	Mutation prevents interaction with streptomycin to S12 ribosomal protein

 

 

Table:2 Second Line Anti-Tuberculosis Drugs:

Drug	Mechanism Of Action	Gene(S) Involved In Resistance	Mechanism Of Resistance
Amikacin And Kanamycin	Inhibition of protein synthesis	Rrs (16S rRNA)	Mutation results decrease in binding of amikacin and kanamycin to 16S rRNA
Capreomycin	Inhibition of protein synthesis	TlyA (2-o-methyl-transferase)	Mutation in tlyA results absence of methylation activity
Paraamino-Salacylic Acid	Inhibition of folic acid synthesis and iron metabolism	thyA (thymidylate synthase)	Mutation in thyA results resistance to paraamino-salicylic acid
Ethionamide	Inhibition of mycolic acid synthesis	ethA and inhA (enoyl ACP flavin monooxygenase reductase)	Mutation in ethA and inhA results resistant to ethionamide and allow continuation of mycolic acid synthesis
Fluoroquinilone	Inhibition of DNA gyrase (topoisomerase-II)	gyrA, gyrB (DNA gyrase)	Mutation in gyrA prevent interaction with fluoroquinolone. Mutation in gyrB and efflux may contribute to resistance
Cycloserine	Inhibit the synthesis of peptidoglycan (cell wall synthesis)	alr (alanine racemase)   ddl (D-alanine ligase)	Mutation in alr and ddc results resistant to cycloserine

 

New Anti-Tuberculosis Drugs:

The combination of new anti-tuberculosis drugs is used for the treatment of tuberculosis to reduce length of the treatment, increase effectiveness of drugs (5).

1.    Bedaquiline:

Bedaquiline is a new drug with specific activity against Mycobacterium tuberculosis. Its is used for the treatment of MDR-TB. Bedaquiline targets atpE gene and inhibits ATP synthase in Mycobacterium tuberculosis (5).

 

2.    Delamanid:

Delamanid is an effective drug against drug-susceptible and drug-resistant mycobacterium tuberculosis. The mode of action is inhibited mycolic acid synthesis by inhibiting methoxy- and keto-mycolic acid (5). Combination of delamanid with rifampicin results in early eradication of Mycobacterium tuberculosis from lungs (2).

 

3.    PA-824:

It is an effective anti-tuberculosis drug and is currently undergoing clinical evaluations. PA-824 is a pro-drug that needs to be activated by a deazaflavin-dependent nitroreductase (Ddn) present in Mycobacterium tuberculosis. It inhibits the synthesis of protein and cell wall lipids of Mycobacterium tuberculosis (5). It is effective against the active Mycobacterium tuberculosis as well as latent Mycobacterium tuberculosis (2).

 

4.    SQ-109:

SQ-109 is an analogue of ethambutol, effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. The mode of action is infecting the assembly of mycolic acids into the bacterial cell wall core. SQ-109 targets on  MmpL3 which is transporter of trehalose monomycolate as a result trehalose mono-mycolate is accumulated, a precursor of the trehalose dimycolate, resulting in inhibition of cell wall biosynthesis (5).

 

5.    Benzothiazinones:

Benzothiazinones is also an effective drug against drug-sensitive and multi-drug-resistant tuberculosis. It inhibits arabinan synthesis needed for the bacterial cell wall (5).

 

 

6.    Novel Fluoroquinolones:

The mode of action of fluoroquinolones is to inhibit two important enzymes (DNA gyrase and Topoisomerase-IV) that are involved in bacterial DNA synthesis (2).

7.    Tetrabenzothiophenes:

The mode of action is to kill mycobacterium tuberculosis by inhibiting protein kinase G (PKnG). In mycobacterium tuberculosis protein kinase G is responsible to block the intracellular degradation of mycobacterium (2).

 

8.    Pyrimidinediones:

The mode of action of pyrimidinediones is to inhibit peptidoglycan synthesis by inhibiting translocase-I. it also binds to the second enzyme Mycobacterium tuberculosis ketol–acid reductoisomerase (Mt-KARI) in the presence and absence of the cofactor, nicotinamide adenine dinucleotide phosphate (NADPH) (2).

Anti-Tuberculosis Vaccine:

Bacillus Calmette-Guerin (BCG) is an effective vaccine against tuberculosis. It is currently used in all over the world to prevent tuberculosis. BCG is a low-cost vaccine, easy to administer, and only one dose is required (2). Mycobacterium tuberculosis induces both humoral immunity and cell-mediated immunity into the host body. Macrophages in BCG vaccinated individuals have more ability to kill intracellular Mycobacterium tuberculosis and increase tuberculosis-specific cell-mediated immunity (6).

DOTS (Directly Observed Treatment, Short Course):

Development of multi-drug resistant tuberculosis (MDR-TB) and extensive drug resistant (XDR-TB) are alarming because of the high mortality rate. To control an alarming situation, DOTS is a highly effective strategy, which is based on five main principles (2):

1.    To establish a system by government that will monitor, record, report tuberculosis and control them.

2.    To diagnose tuberculosis by the microscopic examination of sputum.

3.    Anti-tuberculosis drugs to be given under the observation of health care provider.

4.    Regular supply of short course anti-tuberculosis drugs.

5.    Assessment of treatment results of every individual.

Conclusion:

Tuberculosis is an air-borne infection, transmitted through inhalation of droplet nuclei containing mycobacterial bacilli. The infectious dose is very low as inhalation of 10 mycobacterial cells is responsible to cause pulmonary tuberculosis. The infection of Mycobacterium tuberculosis is spread through coughing, sneezing, talking, singing, laughing etc. The morbidity and mortality rate of Mycobacterium tuberculosis can be reduced by the given combination of anti-tuberculosis drugs, anti-tuberculosis vaccine, immune booster, and by following control and prevention (2).

The rate of tuberculosis infection is high because of close contact between infected person and susceptible individual in household, workplace, public transportation, crowding, picnic spots etc. transmission of tuberculosis can be reduced by social distancing, isolating infected person from healthy persons, proper ventilation in crowding areas (1).

Individuals who have any underlying disease (AIDs, diabetes mellitus, organ transplant, renal dialysis, malnutrition, drugs addiction, alcoholism, smoking) are more susceptible to tuberculosis. Susceptibility can be reduced by treating underlying disease, by reducing the exposure of silica dust, tobacco smoke etc., and by immunotherapy (1).

Infection and the duration of infection can be reduced through early detection, early diagnosis, quicker and more-sensitive diagnostic assays such as Xpert MTB/RIF, improve treatment. Xpert MTB/RIF test was known as GAME CHANGER in the diagnosis of tuberculosis. It has high sensitivity than sputum smear microscopy (1).

 

 By: Aqsa Saeed

 

References:

1.    Churchyard, G., Kim, P., Shah, N. S., Rustomjee, R., Gandhi, N., Mathema, B., ... & Cardenas, V. (2017). What we know about tuberculosis transmission: an overview. The Journal of infectious diseases, 216(suppl_6), S629-S635.

 

2.    Bansal, R., Sharma, D., & Singh, R. (2018). Tuberculosis and its treatment: an overview. Mini reviews in medicinal chemistry, 18(1), 58-71.

 

 

3.    Kaur, T., Sharma, P., Gupta, G., Ntie-Kang, F., & Kumar, D. (2019). Treatment of tuberculosis by natural drugs: a review. Plant Arch, 19(2), 2168-2176.

 

4.    Nguyen, L. (2016). Antibiotic resistance mechanisms in M. tuberculosis: an update. Archives of toxicology, 90(7), 1585-1604.

 

 

5.    Palomino, J. C., & Martin, A. (2014). Drug resistance mechanisms in Mycobacterium tuberculosis. Antibiotics, 3(3), 317-340.

 

6.    Abate, G., & Hoft, D. F. (2016). Immunotherapy for tuberculosis: future prospects. ImmunoTargets and therapy, 5, 37.