African Medicinal Plants that Can Control or Cure Tuberculosis

This review contains a compendium of medicinal plants in Africa that can control or cure tuberculosis. A good number of plant secondary metabolites are reported to have antitubercular activity comparable to the existing antitubercular drugs or sometimes even better. Information regarding the chemistry and pharmacology of plants leads to insight into their structure–activity relationship and potency. A welldefi ned strategy is required to exploit these phytomolecules as antitubercular drugs. Review article African Medicinal Plants that Can Control or Cure Tuberculosis Philip Ifesinachi Anochie1*, Bakoh Ndingkokhar2, Juan Bueno3, Felix Emeka Anyiam4, Linus Ndidi OssaiChidi5, Edwina Chinwe Onyeneke1 and Anthony Chidiebere Onyeozirila1 1TB/HIV/AIDS Research Group, Philip Nelson Institute of Medical Research, Lagos, Nigeria 2Chemical Bioactivity Information Centre (CBIC) Cameroon, Department of Chemistry, University of Buea, South West Region, Cameroon 3Fundación centro de investigación de bioprospección y biotecnología de la biodiversidad BIOLABB, Colombia 4Center for Health and Development, University of Port Harcourt Teaching Hospital, University of Port Harcourt, Nigeria 5Department of Haematology, Blood Transfusion and Immunology, University of Port Harcourt Teaching Hospital, University of Port Harcourt, Nigeria Received: 29 May, 2018 Accepted: 13 June, 2018 Published: 15 June, 2018 *Corresponding author: Philip Ifesinachi Anochie, TB/HIV/AIDS Research Group, Philip Nelson Institute of Medical Research, Lagos, Nigeria, Tel: +2348166582414, +2348140624643, +23473175179; E-mail:

The acetone fraction of the stem bark of C. molle caused complete inhibition at concentrations higher than 1 mg/ mL. Phytochemical analysis of the bioactive fraction led to the isolation of a major tannin and two oleanane-type pentacyclic triterpene glycosides. The tannin was identifi ed as the ellagitannin, punicalagin, whilst the saponins were characterized as arjunglucoside (also called 4-epi-sericoside) and sericoside. All the pure compounds were further tested against the M. tuberculosis ATCC strain. Punicalagin was found to inhibit totally growth of the ATCC and also of a patient strain, which was fully sensitive to the standard antituberculosis drugs, at concentrations higher than 600 g/mL and 1.2 mg/mL, respectively.
Also, in Eastern Cape, South Africa has been assayed antitubercular activity of polyherbal formulations with several medicinal plants active to concentrations between 25-50 μg/ mL [1].
In addition, essential oils have been derived from S. aratocensis, T. diff usa and L. americana, three aromatic plants of Colombia that are active against tuberculosis.

Emergence of new drug resistant variants
A number of antimicrobial agents already exist for various purposes but the search for new antimicrobial agents should be a continous one since the target microorganisms often evolve into new genetic variants which subsequently become resistant to existing agents [2].
The current fi rst line drugs for TB (isoniazid, rifampicin, pyrazinamide and ethambutol) were discovered decades ago and are becoming less effective due to the emergence of drug resistance and the counteractions of HIV infection. Furthermore, effective use of these drugs require months of combination therapy, leading to issues with compliance and signifi cant side effects. Thus, there is an urgent need to discover new TB drugs.
Better and safer drug regimens to shorten treatment is vital in attaining the WHO's ambitious targets of 95% reduction in TB deaths and 90% reduction in TB incidence by 2035 [3].
Natural products of plant biodiversity have received considerable attention as potential anti-TB agents since they are a proven template for the development of new molecules against tuberculosis. Many antitubercular compounds that may prove to be useful leads for TB drug discovery have been derived from medicinal plants [4,5].
Natural product drug discovery works on the basis that biological diversity is the key to chemical diversity [6]. One prerequisite for the discovery of novel bioactive compounds is choosing suitable source material which signifi cantly increases the chance of "hitting a target". Plants have long been viewed as a common source of remedies, either in the form of traditional preparations or as pure active principles. This forms a strong basis to utilize local plants that have been traditionally used as medicine and investigate them for their active chemical constituents [7][8][9][10].

New tuberculosis drug targets
Some selective targets essential to the survival of the microorganism considered in the development of any anti-TB drug include the cell wall which provides protection to the Mycobacteria and is impermeable to a number of drugs, while also conferring inherent resistance [11]. In this way, natural terpenes have the ability of produce microbial cell wall disruption causing lysis [12]. Amino acid and co-factor biosynthesis; targeting the amino acid synthesis and cofactor pathways in the bacteria causes reduced metabolism and reproductive activity in the organisms [13], and DNA metabolism; ribonucleotide reductases are essential to the Mycobacterium and reproduction activities. Equally antibiofi lm activity using Mycobacterium smegmatis 155 mc 2 is a important model for antitubercular activity because biofi lms provides a niche for establish antimicrobial resistance [14,15].

Selected natural products with Anti-Tb prospects
Antimycobacterial bioactive chemical molecules have been found from many natural product skeletons, mainly from plant biodiversity, but also from other organisms, such as fungi and marine organisms. Because natural products are a proven template for the development of new scaffolds of drugs, they have received considerable attention as potential anti-TB agents. A wide range of phytoconstituents are responsible for anti-tubercular activity includes alkaloids, glycosides, tannins, phenolics, xanthones, quinones, sterols, triterpenoids etc. These phytoconstituents present in plant exert desired pharmacological effect on body and thus act as natural anti-tubercular agents. Constituents from Medicinal plants play a key role in drug discovery programs, both serving as drugs and as templates for the synthesis of new drugs. This review summarizes the correlation between the uses of plants in Traditional African medicine against Tuberculosis (TB) and the biological activities of the derived natural products (both extracts and isolated compounds), with the aim to validate the use of traditional medicine against TB in African countries. The study was done by curating data from journals in natural products and phytomedicine. It was observed that the ethnobotanical uses of the plant species surveyed correlated with the bioactivities of the plant extracts and isolated compounds identifi ed. In addition in drugextract combination assays has been possible to determinate synergistic activity of combinations of antimycobacterial drugs with medicinal plants, opening the horizon of new impact studies on traditional medicine uses [16].  [18]. Therefore, several plant species have been used traditionally to treat various diseases/ailments. Traditional medicine has been defi ned by the World Health Organization (WHO) as practices, knowledge and belief systems which use minerals, plants and animal based remedies, spiritual therapies and exercises to prevent, treat and maintain wellbeing [19]. The statement that natural products represent an enormous potential for drugs leads cannot be disputed [20]. This is because natural products often result from an optimized evolutionary process in which chemicals have been under the selective forces of coevolution, organisms producing substances (secondary metabolites) in the presence of their predators for their own defence mechanism and survival.

Socio-economic need of Anti-Tb natural products
These natural compounds (secondary metabolites) have been utilized and chemically modifi ed by humans since ancient times to treat and cure their diseases [21].

Evaluation of the bioactive natural products
In many countries especially in subSaharan Africa, ethnobotanical and ethnomedical knowledge have been greatly exploited to evaluate the antimycobacterial properties of plants in vitro using crude extracts [23,24]. Some crude extracts have shown remarkable antimycobacterial activities against Mycobacterium tuberculosis and other mycobacteria [25].
This review therefore represent a continuation of the survey of the search for anti-tuberculosis agents from African fl ora. This is backed by correlating the biological activities of the isolated metabolites with the ethnobotanical uses of the plant species.
The most used methods in antitubercular in vitro drug discovery have been described as agar dilution, broth dilution, MGIT 960 fl uorescence assay, microplate alamar blue assay (MABA), resazaurin microtiter assay (REMA) and tetrazolium microplate assay [26,27,28]. Also, MBEC™ assay system (MBEC™ Biofi lm Technologies Ltd. Calgary, AB, Canada) has been employed for to evaluate antibiofi lm activity of new drugs so it can be very useful to complement antimicrobial assays of natural products from medicinal plants [29].

Outcome of evaluated bioactive compounds
Interesting results for classes of compounds which exhibit antituberculosis biological activities correlating with the ethnobotanical uses of the plant species of origin have been widely obtained.
Tabernaemontana elegans (toad tree) is an alkaloid which has been reported to be used traditionally by the Venda and Zulu people of South Africa: a root decoction is applied as a wash to wounds, and drunk for pulmonary diseases and chest pains [30]. It has been previously reported that extracts of this plant has demonstrated antibacterial activity against S. aureus and antimycobacterial activity against M. smegmatis [31].
Lippia javanica (Verbenaceae) is an aromatic herb that occurs all over Mozambique. Infusions of its leaves is commonly used in Africa as tea against various ailments like infl uenza, measles, rashes, malaria, stomach problems, fever, colds, cough, headaches [32] and isolated triterpene euscaphic acid from this plant [33]. This compound was tested against Mycobacterium tuberculosis, it was found to exhibit a minimum inhibitory concentration of 50 μg/mL against sensitive strain of M. tuberculosis, H37Rv, reference strain (27294).
The plant species A. afra (commonly called African wormwood) is widely distributed in South Africa from the Cederberg Mountains in the Cape, northwards to tropical East Africa [34]. This plant is reported to be used to treat coughs, colds, diabetes, malaria, sore throat, asthma, headache, dental care, gout and intestinal worms in South Africa [35]. In vitro studies of A. afra extracts have revealed that the plant is a potential antidepressant, cardiovascular, spasmolytic effects, antioxidant, and antimycobacterial [36]. growing amongst rocks in grassland [45]. The plant has found a wide variety of medicinal applications in treating colds, bronchitis, tuberculosis, coughs, asthma, feverish headaches, and dysentery and chest infections [30]. It was identifi ed as a potential source of novel anti-tuberculosis compounds.
The organic extracts of this plant showed greater than 99% growth inhibition against Mycobacterium tuberculosis when tested at 1000 mg/ml with rifampicin as the positive control (2 mg/ml), and was considered to have potent activity against Mycobacterium tuberculosis [46], which correlate to it application in traditional use. Green [48]. Prenylated fl avonoid [49], and other secondary metabolites including friedelin, epifriedelin and phenolic derivatives such as gallic acid, ellagic acids, anthocyanidin, taraxerol, taraxerone and caffeic acid have been isolated from these plants species [50]. And generally, fl avonoids are known for their antituberculosis properties [51].

Challenges of developing Anti-Tb drug from plants
The classic pathway towards anti-TB drug discovery from natural products and other infectious diseases must overcome a number of challenges.
The fi rst is to reliably detect effi cacious and safe hits and be able to identify already known compounds at the early stages of the drug discovery program.
The second major challenge is the de novo structure elucidation of new molecular entities. Though current advances in spectroscopic techniques, specifi cally the high resolution neutron magnetic resonance (NMR) technologies have been contributed to the resolution of this challenge. Many approaches have been developed to solve the major hurdle, but it still remains a major challenge in anti-TB drug discovery from natural products [55]. Innovative technology is needed to impact the early phases of anti-TB drug discovery from natural products, innovative technologies need to be leveraged for
Considering that none of the several screened nonmicrobial natural products with activity against MTB has progressed towards the clinical trial stage in anti-TB drug development, this could possibly be caused by: i. Low yields of purifi ed compounds; ii. Structural complexity exhibited by natural products, such as the occurrence of multiple stereoisomers, e.g., triterpenes which contain ten or more chiral centers; iii. Low activity exhibited by the isolated compounds with Finally is very important take in account that in antimicrobial Berchemia discolor Rhamnaceae (3 S)-discoloranone Infertility and Menorrhagia Antimycobacteria [66] Peltophorum africanum Fabaceae Catechin (fl avonoid), bergenin, betulinic acid Used to treat tuberculosis, stomach complains and intestinal parasites Antimycobacteria [73] drug discovery from natural sources the endpoint criteria for activity should be below 100 μg/mL for crude extracts and 25μM or 10 μg/mL for pure compounds with the end of select new promisory antimycobacterial treatments [57,58].

Conclusion
It will be diffi cult to resolve the aforementioned challenges without increased funding for anti-TB drug discovery and construction of a more robust drug development pipeline through well-coordinated international efforts. Plants are sole treatment of leprosy and tuberculosis in some African countries. Though anti-mycobacterial MIC of plant materials is higher but they have resistance modifying properties. Therefore, plant derived drugs can help in fi ghting the drug resistance. Unfortunately, there is no plant derived molecule either in market or under trial for treatment of mycobacterial infections. Majority of studies focused on identifi cation of crude plant extracts with anti-mycobacterial properties and has not been extended to identifi cation of bioactive plant metabolites.
Therefore, an integrated approach of identifi cation of plants with anti-mycobacterial activity followed by identifi cation of bioactive molecule will speed up the research and development of plant derived drug molecules for mycobacterial infections.