Traditional Medicinal Plants as a Source of Antituberculosis Drugs: A System Review

Medicinal plants are the chief components in the different oriental formulations in different traditional medical systems worldwide. As a thriving source of medicine, the medicinal plants with antituberculosis (TB) properties inspire the pharmacists to develop new drugs based on their active components or semimetabolites. In the present review, the anti-TB medicinal plants were screened from the scientific literatures, based on the botanical classification and the anti-TB activity. The obtained anti-TB medicinal plants were categorized into three different categories, viz., 159 plants critically examined with a total 335 isolated compounds, 131 plants with their crude extracts showing anti-TB activity, and 27 plants in literature with the prescribed formula by the traditional healers. Our systemic analysis on the medicinal plants can assist the discovery of novel and more efficacious anti-TB drugs.


Introduction
Globally, traditional medicines (TM) make a vital contribution to the health care industry. In some countries, TM is the main source of health care or even the sole health care service available, especially in the rural sector [1]. The popularity of TM is also increasing in the developed countries for many different reasons, one of which is that the effectiveness of these TM was proved by the ethnopharmacological research. Early in 1972, the World Health Organization (WHO) established a Department of Traditional Medicine (DTM). Later, WHO (2013) called on to strengthen its public services of the traditional medicine [1]. Recently, the International Classification of Traditional Medicine (ICTM) was added as a new chapter into the International Classification of Diseases-11 (ICD-11) [2]. This achievement currently refers to the Traditional Chinese Medicine (TCM) alone, which opens its doors to accommodate many other thriving traditional health care philosophies prevailing glob-ally, such as Ayurveda and Traditional African medicine (TAM).
The spread of tuberculosis (TB) occurred from East Africa to the rest of the world with the migration of Homo sapiens, especially along the established trade routes with increased mingling and crowding of populations [3,4]. Currently, there exist more than 10 million new cases of active disease and nearly 1.3 million deaths annually [5,6]. In response to this spreading route, different countries developed their own traditional anti-TB formulations during the long courses in fighting this old plaque. Reports relating TB can be found in many ancestral data of the TM medical system, especially the TCM, Ayurveda, and TAM for its long history coexisting with human kinds for an estimated 70,000 years [7]. Investigations on the TM formulations show that the plants or herbs are the main composition of the traditional anti-TB formula, from which the active components or semimetabolites present a thriving source of new drugs. In the last 20 years, nearly 50% of drugs approved by the FDA in the United States of America have been derivatives of the natural products, including natural plant products [8]. Among the 435,000 plant species reported worldwide [9], an estimated 70,000 species of plants are used for medicinal purposes [10]. Thus, selecting plants based on ethnobotanical knowledge can enhance the probability to find new compounds with anti-TB activity.
Before this review, some articles summarized the role of local medical plants but only few with anti-TB purpose [11,12]. In this review, the anti-TB medicinal plants in different countries or regions are included to analyze their botanical classification, active botanical parts, extract method, and in vitro anti-TB activities in brief. Subsequently, the effective anti-TB plants are described with the following three branches: those with the isolated effective compounds, those with their crude plant extracts showing anti-TB effect, and those only found in the formula prescribed by traditional healers. Finally, we discuss the influencing factors on the development of traditional medicine and its future trend. This review is to inspire the development of possible new anti-TB agents derived from plants.

Brief Description of the Overall Anti-TB Medicinal Plants
We present the data by searching the main three databases: Wangfang Med, Chinese National Knowledge Infrastructure, and PubMed. Combinations of the following search terms are used: "tuberculosis," "plant," "herb," "Chinese and western medicine," and "random." In the present review, only the nonrepetitive plant species with good in vivo or in vitro anti-TB effect were accepted, although the criterion of the effectiveness was quite different with the inhibition concentration expressed in several different ways in different Mycobacteria, especially the M. tuberculosis H37Rv and the clinical isolates. The plants employed for treating the fever in traditional medicine have not been included, as fever is taken to be a nonspecific indication of many infections that are not restricted to TB. The exception to this is where fever is treated in conjunction with other TBrelated symptoms like coughing. The classification of the traditional anti-TB medicinal plants in the present review belongs to 90 families including 230 genus and 277species ( Figure 1). The top 11 families with more than 7 plant species include Fabaceae (21 species in 18 genus), Asteraceae (20 in 16 genus), Euphorbiaceae (14 in 11 genus), Lamiaceae (13 in 11 genus), Rutaceae (14 in 10 genus), Combretaceae (9 in 4 genus), Piperaceae (9 in 1 genus), Zingiberaceae (8 in 3 genus), Annonaceae (7 in 6 genus), and Apiaceae (7 in 7 genus). Forty plant families are only reported once. A total of 6 Terminalia genus that belongs to the Combretaceae family have up to 6 anti-TB plant species, and about 9 anti-TB plant species belong to only one genus Piper.
The literatures that we studied reported the anti-TB properties of the plant species from different plant parts (aerial parts, almonds, bark, bulbs, branches, fruits, flowers, heart woods, leaves, rhizomes, roots, stems, seeds, shoots, twigs, tubers, wood, whole plants, and even the ethnomedic-inal recipes). With the leaves (83 cases), roots (61), aerial parts (32), barks (30), stems (14), whole plants (9), seeds (9), fruits (8), rhizomes (8), and flowers (7) are the top 10 most used anti-TB plant parts. For the same plant species, different parts of the plant presented a varied anti-TB effect. The useful plant parts of the genus Lantana, Piper, and Terminalia mainly focused on the leaves, leaves, and both leaves and roots, respectively.
It was observed that the extraction methods of the medicinal plants available in the literature significantly affected the anti-TB results. The general problems concerning the antibacterial screening of medicinal plant extracts have already been discussed in the literature [13]. There is still no single extraction method that is regarded as a standard for extracting the bioactive compounds from medicinal plants. One or more of the following solvents were mainly used in the studies: dichloromethane (268 times), methanol (65), ethanol (45), hexane (29), chloroform (18), ethyl acetate (11), water (11), and acetone (10), while diethylether, acetate, and hydroalcoholic solutions were seldom used. Since the extraction process deeply influences the results of the bioactivity tests and the subsequent isolation of bioactive compounds, selection of the best extraction method by consulting the traditional knowledge about the preparation of the herbal remedy remains crucial [14].
As noted earlier and evidenced by this review, many reports lack adequate statistical analysis of their results and appropriate controls for their anti-TB activity, while some studies lack the generic extraction schemes or tests against a panel of various species of Mycobacteria to avoid false positive results. In this review, the parallel cytotoxic evaluation on mammalian cell lines has not been provided, since our main aim was to summarize the crude extracts or compound precursors of the anti-TB medicinal plants, although this needs to be overcome in the future.

Compounds from the Plants with Anti-TB Activity
Different from the conventional process of drug discovery involving the screening of large molecular libraries for biological activities and/or in silico data mining approaches based on cheminformatics modeling, the bioactivity-guided fractionation was mostly employed in medicinal plants to isolate the bioactive compounds. They were extracted first from the specified parts of the plants, then fractionized and characterized by infrared spectroscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy, to obtain the structural data. Finally, their bioactivities were verified in different mycobacteria. Several groups summarized the active anti-TB natural products from the different organs and regions. Early in 2007, Copp and Pearce [15] summarized a total of 353 natural products (secondary metabolites) with reported growth inhibitory activity towards M. tuberculosis or related organisms from terrestrial and marine plants and animals and microorganisms. Abedinzadeh et al. [16] stressed the natural antimycobacterial peptides from bacteria, fungi, plants, and animals. Chinsembu [17] described the natural the 335 compounds are sorted out in Figure 2. Of all the anti-TB natural compounds, the derivatives and analogs of phytol, flavones, and terpenoids were critically reviewed by Singh et al. [173] and Cantrell et al. [174] for their pharmacological activities of various diseases. These 335 compounds were natural products or secondary metabolites, and few of their synthetic modified derivatives have been mentioned in this review.

Plants Showing Anti-TB Effect in Form of Crude Extracts
The plants whose active components were isolated and tested for their anti-TB activity as described in Section 3. This section summarizes the reported plants for their anti-TB activity only in the form of crude extracts. They are listed in Table 2 with the total amount of 128 plant species. The top five plant families were Asteraceae, Euphorbiaceae, Fabaceae, Piperaceae, and Acanthaceae, and the plant parts mainly used for extraction were root for Fabaceae family and leaf for Asteraceae, Piperaceae, and Acanthaceae, respectively. For Euphorbiaceae family, the plant parts of bark, fruit, leaf, root, and seed were reported with the anti-TB function.
Among the extraction methods, ethanol, hexane, and methanol were found to be the top three frequently used  Andrographis paniculata Acanthaceae Leaf Ethanol extracts with inhibition of mycobacterial (standard and clinical) growth [7,190] Angiopteris evecta Marattiaceae Leaf 80% methanol extract against M. tuberculosis H37Rv ATCC 25618 with an MIC of 400 μg/ml [191] Apodytes dimidiata Icacinaceae Leaf Hexane extractions against the field strain of MDR-TB and against the M. tuberculosis H37Rv with MIC of 0.47 and 0.31 mg/ml, respectively [192] Artemisia ludoviciana Asteraceae Bark, leaf Hexane extracts against MDR-TB clinical isolates with MIC of 25-100 μg/ml [58,193] Artemisia nilagirica Asteraceae Leaf Ethanol extracts against M. smegmatis with IC50 c of 300 μg/ml [194] Beilschmiedia obscura Lauraceae Root Ethyl acetate extracts against M. tuberculosis H37Rv with MIC of 31.25 μg/ml by MABA b [195] Bidens odorata Asteraceae Aerial parts
To date, no specific cut-off value has been established as a reference to analyze the anti-TB activity results of the plant extracts, and many different methods are available to evaluate the activity. As of date, only a few anti-TB plant extracts in Table 2 have been tested in preclinical or clinical trials. It is encouraging that more and more promising crude extracts are now paving a way for the clinical test for their therapeutic applications. This section can provide a new perspective   [191] 25 BioMed Research International in expanding the anti-TB plant species for the development of anti-TB medicine in the future.

Medicinal Plants Only Found in Formula Prescribed by the Traditional Healers
Traditional healers continually serve the public health in most of the countries. Some ethnomedical information has been published based on many plant species in anti-TB formulas documented by different traditional healing systems, ranging from the poor documented oral African medicine to the well-documented Ayurveda or Chinese medicine. These reports inspired the scientists to find more effective compounds for tuberculosis. The investigations of medicinal plants using frontier technologies are now being reconsidered to be a feasible approach for discovering novel bioactive compounds and crude extracts, in order to solve the wide spreaded TB problems. Table 3 shows the main species or families of the traditional plant medicines and their botanical details in the published papers by the systemic survey of the prescribed formula, but very few studies reveal the working compounds or active crude extracts. The anti-TB formulas were investigated in many countries or regions, such as China, India, Mexico, South Africa, Pakistan, Iraq, Malaysia, Congo, Lao PDR, Nigeria, Nigeria, Burundi, Papua New Guinea, Lake Victoria Basin (Uganda, Kenya, and Tanzania), Arabian Peninsula, Southeast Asian, and Manus Province. Most anti-TB formulas were found during the ethnopharmacological investigation of the indigenous plants. To strengthen the anti-TB purpose, the present review summarized the anti-TB plant in the formula from the ethnopharmacological publications, with an emphasis on their classification (Table 3). Although three reports in Table 3 did not show the botanical family of the anti-TB medical plants in detail, it still can be speculated that the family Fabaceae is the most represented species, followed by Asteraceae, Euphorbiaceae, and Liliaceae families.
We need to be aware that the plant medicine used by the traditional healers is based on their according ethnomedical traditional medical theories. In comparison with the western system of medicine, the traditional plant medicines showed certain drawbacks. An important issue of all was that the active components of the herbal drugs prescribed were unknown. The activity of the traditional herbal drugs prescribed by the traditional healers can be greatly affected by the difference in the processing methods, variation in the potency due to difference in plant species and subspecies, varying geographical location of growth, nonuniform quality control standards, etc. Furthermore, for a given plant, a specific place, part, method, and time for collection can significantly affect the therapeutic efficacy [16,40]. Hence, the plant medicine used by the traditional healers needs a critical evaluation to find the active components.

Need for Future Research
Although this review presents a big list of plants with effective anti-TB activities from different traditional medicine systems, there is a need of better therapeutic drug monitoring systems and high throughput in vitro assays for the routine screening to identify potentially serious and clinically significant herb-drug interactions [262]. Furthermore, there is a lack of in vivo information regarding the drug metabolism associated interactions with reference to the traditional medicines and the treatment of TB. This requires health care practitioners to ensure a clear communication with patients regarding the possible negative impacts of simultaneous use of certain TMs and prescribed drugs. It was reported that the widely used Sutherlandia frutescens in the treatment of TB in countries of Southern African Development Community interfered with the isoniazid therapy, but the mechanism of this interaction was not clear [263,264]. Coadministration also resulted in the reduced bioavailability of ofloxacin [265], while piperine showed the ability to increase the bioavailability of the antituberculosis drug rifampicin [266][267][268].
Several issues affect the anti-TB activity of the components of the medicinal plants, such as the variation in the potency due to difference in species, absence of an integrated coding for every species used commonly in TMs, varying geographical location of growth and incorrect identification of drugs, and nonuniform quality control standards [269]. No clinic trial was reported on the crude extracts, and even the pure compounds from the medical plants still need to be elucidated for their constituent characterization and the mechanism of action. Till date, not many compounds have been originated from plants for further modification for use in clinic. We hope that this review will help to find a possible way to get better anti-TB results by making a combination of the compounds originated from plants based on the different TB-killing mechanisms.

TB:
Tuberculosis TM: Traditional medicines Emergence of extensively drug-resistant TDR: Total drug-resistant MIC: Minimum inhibitory concentration MBC: Minimum bactericidal concentration MIA: Minimum inhibitory amount IC 50 : Half maximal inhibitory concentration MABA: Microplate alamar blue assay.

Data Availability
All data included in this article are available from the corresponding author upon request.

Ethical Approval
Ethical approval is not applicable.

Consent
Consent was not necessary.

Conflicts of Interest
The authors declared that there are no conflicts of interest.

Authors' Contributions
ZS and YX designed and organized the review. CK drafted the manuscript. BL revised the manuscript. All authors read and approved the final manuscript.