Natural Remedies against Multi-Drug Resistant Mycobacterium tuberculosis

Ramesh Pandit, Pawan Kumar Singh^*, Vipin Kumar

Value Addition Research and Development Department-Human Health, National Innovation Foundation (NIF)-India, Ahmedabad, India.

DOI: 10.4236/jtr.2015.34024                

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis is an infectious deadly disease and the treatment of which is one of the most severe challenges at the global level. Currently more than 20 chemical medications are described for the treatment of TB. Regardless of availability of several drugs to treat TB, the causative agent, M. tuberculosis is nowadays getting resistant toward the conventional drugs and leading to conditions known as Multidrug-resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB). This situation has terrified the global health community and raised a demand for new anti-tuberculosis drugs. Medicinal plants have been used to cure different common as well as lethal diseases by ancient civilizations due to its virtue of variety of chemical compounds which may have some important remedial properties. The aim of the present review is to focus the anti-tubercular medicinal plants native to India as well as the plants effective against MDR or XDR-TB across the globe. In the present review, we have addressed 25 medicinal plants for TB and 16 plants effective against MDR-TB testified from India and 23 herbal plants described for MDR-TB across the world during 2011-2015. These herbal plants can serve as promising candidates for developing novel medications to combat multidrug resistant M. tuberculosis.

Keywords

Drug Resistant, Mycobacterium tuberculosis, Medicinal Plants, MDR or XDR-TB

Received 3 November 2015; accepted 18 December 2015; published 22 December 2015

1. Introduction

Tuberculosis (TB), an infectious deadly disease caused by the various species of Mycobacterium, especially Mycobacterium tuberculosis, was emerged from East Africa more than three million years ago [1] .

According to World Health Organization (WHO), TB is the second most fatal disease after HIV, accountable for human death across the globe and about one third of human population is estimated to be infected with M. tuberculosis. However, it is not necessary that all infected person may get the tuberculosis. The carrier stage is called latent tuberculosis, in which M. tuberculosis infected person does not show any symptoms of disease. Still, about 5% to 10% of the infected people have a chance to develop TB, depending upon the immunity of the individual. Around 6.1 million TB patients have been reported in year 2013, of these, about 5.7 million (93%) cases were new. About 9 million people were reported ill due to TB in 2013, of which approximately 1.5 million died due to the disease (Figure 1) [2] . The disease is highly progressive in Asia and Africa and more than 80% of all TB cases were reported from these two continents [3] . When we talk about Indian scenario, one report said that TB was reported about 3300 years ago [4] while according to ancient literature [5] TB have been reported since 1500BC. Treatment of TB is one of the most severe challenges at the global level. Presently, there are more than 20 drugs which are described for the treatment of TB [6] among them. Isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin are most commonly used.

However, recent few years have revealed that the causative agent of Tuberculosis, M. tuberculosis is getting resistant towards conventional drugs used for treatment. The development of drug-resistant in M. tuberculosis has frightened the global health community [8] [9] . Multidrug-resistant tuberculosis (MDR-TB) is a condition where the M. tuberculosis strain is resistant to two most frequently used drugs i.e. first-line oral (Table 1) specifically isoniazid, rifampicin and it was first developed in USA during 1990s [10] [11] . The improper use of antimicrobial drugs, early treatment cessation, genetic mutation in M. tuberculosis, an inadequate administered treatment, etc. may cause drug resistance [12] [13] which can then be transmitted to other people in the community. Among all, genetic mutation is the most important cause for the MDR-TB and 7 hotspots loci have been identified across the chromosome which includes RNA polymerase beta subunit gene, rpoB (rifampicin), nicotinamidase, pncA (pyrazinamide), catalase-peroxidase gene, katG (isoniazid); inhibin alpha, mabA(fabG1)-inhA (isoniazid), DNA gyrase subunit A&B (quinolone), and 16S rRNA gene, rrs (streptomycin) [14] [15] . According to WHO, around 480,000 cases of MDR-TB were reported in 2013-14 and between 20% to 30% of the new cases were from Soviet Union countries. MDR-TB treatment requires the use of second-line drugs (SLDs), which are less effective [6] and highly expensive compared to first-line drugs [16] . Other drugs which are recommended for TB treatment includes sulfamethoxazole and mefloquine, however, both the drugs require further validation [17] . Recently two new anti-TB drugs, bedaquiline which affects the proton pump for ATP synthase and delamanid which blocks the synthesis of mycolic acids have been approved by the US Food and Drug Administration and European Medicines Agency [18] [19] . Together with MDR-TB, XDR-TB (extensively drug resistant tuberculosis) has also been described where M. tuberculosis is resistant to at least four of the core anti-

Figure 1. Percentage of new TB cases with MDT-TB in 2013-2014 [7] .

Table 1. First and second line recommended by WHO [7] .

TB drugs including, isoniazid, rifampicin and any of the fluoroquinolones and to one of the three injectable second line drugs (Table 1). Nowadays completely drug?resistant Mycobacterium tuberculosis strains have also been evolved which are resistant to all the first and second line drugs used for TB treatment [20] - [22] . Types of report have directed attention of researchers worldwide to find a novel potent drug molecule for the treatment of TB. Recently, [23] researchers have reviewed new drugs for tuberculosis including PA-824 (Nitroimidazole), Linezolid (Oxazolidinones), Sutezolid (Oxazolidinones), AZD5847 (Oxazolidinones) and SQ109 (1,2-diamine). Most of these drugs are under the clinical trial phase II. Therefore, there is an urgent demand to find out some potential anti-tuberculosis medicines which are effective against the resistant deadly strains. As usual, the “hope for the best” is the natural system and generally mankind is always looking into actinomycetes [24] - [26] , fungi [27] [28] , cyanobactria [29] and plants [30] [31] for the new drug molecules. Various drugs have already been identified and still being identified from the natural resources by the mankind.

Further, the interest in herbal medications is due to adverse effect of chemical based anti-TB drugs on the patients, who generally have to administer the drug for longer durations. The adverse effects of first-line oral and second line drugs are summarized in the Table 2. According to one survey in India, the adverse drug reactions during MDR-TB treatment ranges from 57.14% to 94.3% and the most common adversarial effect was found to be gastrointestinal problems (71.7%) [32] . In contrast to this, herbal medicines are naturally occurring chemical compounds which can be administrated in the form of whole plant or it particular part. The advantages of herbal medications are fewer side effects, affectivity in multiple diseases as they are crude mixture of many plant compounds and are low cost.

2. Medicinal Plants for Tuberculosis

The significance of plants has been recognized and documented since ancient time due to virtue of its variety of chemical compounds, which may have some important medicinal properties that can be used to cure diverse diseases. Medicinal plants have been widely used as preventives and curative solutions against different common as well as lethal diseases by ancient cultures. There are some prehistoric data available, in which recipes for medicine preparation from the plants have been discussed [35] - [38] . The World Health Organization (WHO) estimated that about 80 percent of world’s population still relied on traditional medicinal plants for their primary health care. The uses of herbs and herbal products have been broadly being accepted in our modern way of life. Moreover [39] , the majority of new drugs introduced in the United States are derived primarily from the plants. As discussed, most of the chemical drugs cause adverse effects and are costlier, therefore, nowadays there is an increasing inclinations towards the use of an alternative source of medicine, especially based on medicinal plants [40] . A number of medicinal plants have been reported for anti-mycobacterial activity across the globe [41] - [46] .

Ayurveda, means the science of life (Ayur = Life, Veda = Science), is an ancient medical knowledge which was developed in India thousands of years ago and describes numerous plants to treat several diseases. When we particularly talk about TB, more than 250 medicinal plants from India have been reported [47] [48] . The comprehensive safety, toxicity and clinical studies are needed for these plants before using them effectively as curative and/or preventive medications against TB. Table 3 summarizes the Indian plants reported for anti-mycoba- cterial activity during last 5 (2011-2015) years.

Table 2. Adversarial effects of commonly used anti-mycobacterial drugs [33] [34] .

Table 3. Indian medicinal plants possessing anti-mycobacterial activity (Reported during 2011-2015).

The above data shows that some plants and/or their fractions have very low MIC value (>25 µg/mL) (Table 2) and are effective. These plants are promising candidates to find novel medication for the treatment of TB. However, the emergence of MDR and XDR-TB has further inspired the scientific community to find novel and more potent anti-mycobacterial drug molecules. Various plants across the globe possess anti-mycobacterial activity against MDR-TB [67] - [70] . Table 4 summarizes the medicinal plants having anti-mycobacterial activity against MDR-TB reported during 2011-2015 in countries other than India.

India is also one of the leading countries in herbal medicines and researchers are continuously engaged in searching novel drug molecules to combat MDR/XDR-TB. Since last few years several plants have been reported for their anti-mycobacterial activity from India (Table 5).

The review suggests that many plants either confined to India or elsewhere have the unique capability to counter the deadly tuberculosis pathogen. Some plants showed very low MIC values against the clinical isolates of MDR-M. tuberculosis and few of them were also found effective against XDR-TB. These plants surely must be chosen for further researches and attempts should be made to translate this knowledge into some potential anti-TB therapies, either curative or preventive. In some cases the active molecule(s) need to be identified and where the molecule has been identified one should go for generation of safety, efficacy, pharmacokinetics, stability, etc. data through approved clinical experiments, which are essential for drug development, regulatory approval and commercialization. In few studies, it was also observed that most of the data required by the regulatory authorities are available and if some more efforts are made to find out evidences of safety, stability, etc. then these herbal leads may be converted into an alternative and novel solutions to combat MDR and XDR-TB in future.

Acknowledgements

Authors are grateful to Prof. Anil Gupta, Executive Vice Chair, National Innovation Foundation India for his

Table 4. Medicinal plants having anti-mycobacterial activity against MDR-TB reported during 2011-2015 in countries other than India.

Table 5. Indian medicinal plants effective against MDR-TB.

honorary guidance and encouragement for carrying out research activities.

NOTES

^*Corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

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