Plants as Future Source of Anti-Mycobacterial Molecules and Armour for Fighting Drug Resistance
Kundan Kumar Chaubey
Jagdip Singh Sohal
Mycobacteria are dreadful human and animal pathogens causing range of mycobacterioses in different tissues. Due to their cell wall composition and their adaptability mycobacteria can survive in different habitats for years. Emergence of Multi-drug Resistant (MDR) and extensively drug resistant (XDR) strains has complicated the problem of mycobacterial disease control. Therefore new drugs should evolve to fight drug resistance. Medicinal plants may offer a new hope as source of bioactive molecules for developing alternative medicines for the mycobacterial diseases. Presently used anti-mycobacterial medicines produce serious side-effects and cannot be used in animals because of risk of entry into food chain. Plant derived medicines may help solving this problem and fighting the drug resistance. The present study reviews the literature available on anti- mycobacterial plants and their bioactive molecules with hope that this effort will expedite the research on development of a novel plant derived drugs against mycobacterial diseases.
to cite this article:
Brajesh Singh, Mukta Jain, S.V. Singh, Kuldeep Dhama, G.K. Aseri, Neelam Jain, Manali Datta, Neeraj Kumar, Parul Yadav, Sujata Jayaraman, Saurabh Gupta, Kundan Kumar Chaubey and Jagdip Singh Sohal, 2015. Plants as Future Source of Anti-Mycobacterial Molecules and Armour for Fighting Drug Resistance. Asian Journal of Animal and Veterinary Advances, 10: 443-460.
World Health Organization (WHO) has stated that 80% of the worlds population depends on traditional medicine for primary health care (Hiremath and Taranath, 2013). Rising cases of resistant pathogenic strains has caused a focus to develop plant derived antibiotics. Plant derived medicines are supposed to absorb easily in the body and cause less or no side effects (Sibanda and Okoh, 2007). Though Minimum Inhibitory Concentrations (MICs) of plant based antimicrobials is generally higher than antimicrobials obtained from microorganisms, but they have resistance modifying properties (Sibanda and Okoh, 2007). Venkitanarayana (2014) has stated that the plant derived antimicrobials contain different functional groups, hence, their antimicrobial activity is attributed to multiple mechanisms, thereby limiting the development of bacterial resistance against these compounds. Therefore, plants provide a great hope for fighting against antimicrobial resistance.
Plant secondary metabolites can affect the microbial cell in several ways; the disruption of membrane function and structure, interference with DNA replication, interference with RNA transcription and protein synthesis, coagulation of cytoplasmic contents, interruption of quorum sensing, interference with metabolic processes, interference in gene regulation and inhibition of cell wall synthesis enzymes etc (Radulovic et al., 2013). However, literature on the antimicrobial action of plant metabolites shows that cell membrane is their primary target (Ahmad et al., 2011; Deva, 2010). They may affect its structural integrity, permeability or functionality. It has been shown that the action of plant metabolites as antibacterial agents increases with their increasing lipophilicity, which may be attributed to fact of their increased ability to interact with the cell membrane (Sikkema et al., 1995).
Antimicrobial potential of plant metabolites is influenced and dependent on factors like; type of target cell (bacterial/fungal cell, gram-positive/gram-negative bacteria) and also the environment conditions-hydrophilicity (i.e., solubility in water), concentration, temperature and pH (Denyer and Stewart, 1998). Therefore, it may be predicted that action of plant metabolites is expected to be similar for gram-positive bacteria and fungal organisms, where the main target is the cell envelope, whose disintegration or changes in permeability are followed by an efflux of the intracellular compounds and coagulation of cytoplasm (Kalemba and Kunicka, 2003). Plant metabolites can also reduce the production of bacterial and fungal toxins (Rammanee and Hongpattarakere, 2011; Filgueiras and Vanetti, 2006; Daifas et al., 2004). One of the very important features of the plant metabolites in fighting microbial diseases is inhibition of quorum sensing. It has been shown that many plant metabolites are inhibitors of quorum sensing (Koh and Tham, 2011; Pan and Ren, 2009). Quorum sensing is the important tool employed by microbial pathogens during virulence like production of toxins, biofilm formation etc.
Interesting observation is that many plant extracts are reported to enhance the activity of several available antibiotics (Adwan and Mhanna, 2008; Braga et al., 2005). Therefore, many plant-derived compounds have been evaluated not only for their antimicrobial activity, but also for their action as potentiators of antibiotics and as reversal antibiotic resistance. Hence, plant extracts or metabolites can also be used as antibiotic coadjuvants to enhance their activity as well as reverse the antibiotic resistance. Plant extracts are supposed to enhance the antibiotic activity due to multi-target effect (Ulrich-Merzenich et al., 2009). Majority of thoroughly studied medicinal plants contain broad spectrum of bioactive compounds (Efferth and Koch, 2011) with each phytochemicals have different antimicrobial mode (Simoes et al., 2009). Multitarget effects of phytochemicals include alteration in structure and function of proteins, interference with synthesis of DNA or RNA or proteins, disruption of the cell membrane and change in its function, inhibition of cytochrome P450 or enhanced absorption and thus bioavailability of active metabolites (Efferth and Koch, 2011; Wink, 2008).
It has been shown that extracts of different plants contain inhibitors of efflux pumps in bacteria (Garvey et al., 2011; Hsieh et al., 1998), therefore can help fighting multidrug resistance by inhibiting the action of efflux pumps. Another strategy to overcome resistance is to improve the delivery or enhance the accessibility of antibiotics to their sites of action. Many plant metabolites have been reported to affect membrane permeability of a diverse range of microorganisms (Helander et al., 1998), mainly due to the disturbances in lipids of the cell membrane. Also, because of their lipophilic nature, they can increase membrane permeability (Trombetta et al., 2005). Therefore, plant metabolites can enhance the permeability of bacterial cells to exogenous products, including antimicrobial agents and hence potentiate the antibacterial activity of antibiotics (Simoes et al., 2009). Potentiation of antibiotic action by plant metabolites may also be done by inhibition of biofilm formation. It is well known that bacteria in biofilms are more resistant compared to individual cells. Biofilms constitute a major threat in the clinical environment by acting as reservoirs of multidrug resistant bacteria. As mentioned in previous paras, quorum sensing regulates the formation of biofilms, as plant metabolites can inhibit the quorum sensing therefore will inhibit the formation of biofilm and thereby help in fighting drug resistance.
Plant materials have been used to promote the animal/ human health by strengthening the host defenses. Therefore besides antimicrobial properties, plants are also fascinating to scientists for their immune-modulatory effects on host. A number of plants have immune modifying properties. These immune modifying properties can help clearing infections by boosting the host innate defenses and promoting immune reactions against pathogens. Plants have been shown to have various immune-modulatory effects including; enhancing phagocytosis, enhancing lysosomal activity, stimulating release of cytokines, enhanced antibody production, stimulation of immune cells (CD4, CD8, macrophages etc), enhance expression of MHC molecules, increases activity of NK cells, enhances NO and superoxide production in macrophages etc (Mahima et al., 2012; Dhama et al., 2014; Mukherjee et al., 2014). Therefore, plant materials not only exert antimicrobial effects but also boost the immune system for clearing the infection.
Mycobacterial infections are chronic (like leprosy, tuberculosis, bovine tuberculosis, paratuberculosis, etc) diseases and control of these diseases is a daunting task in several ways (Singh et al., 2014a). Firstly, there are no specific clinical symptoms in affected individuals. Secondly, lack of sensitive and specific diagnostic tests to identify mycobacterial infection in sub-clinical stage. Thirdly, lack of effective vaccines for preventing these diseases. At present, the chemo-therapeutic options for mycobacterial diseases are extremely few and cannot be used in animals due to concern of entry of these drugs in food chain through milk and meat (Ayele et al., 2001). Therefore, phytomedicine based approach if implemented in modern anti-mycobacterial therapies can be helpful in reducing the incidence of mycobacterial infections both in humans and animals, especially in current era of emerging antibiotic resistance (Tiwari et al., 2013). The present review is a compilation on the data available on testing of plants for the anti-mycobacterial activity as wells as ethno-medicinal data with an objective to raise awareness for treating human and animal mycobacterial diseases with plant derived drugs.
Tuberculosis: Tuberculosis (TB) is a fearful disease in developing nations especially in the Asian and African continents, mainly due to insufficient means of disease management. Globally nine million people get tuberculosis and two million people die from it (Anonymous, 2014). These numbers are likely to increase because the Human Immunodeficiency Virus (HIV) is knotted with tuberculosis and also due to the evolution of multidrug-resistant strains. India alone account for 24% of total tuberculosis cases worldwide. It is scary to note there are estimated 2,10,000 deaths from MDR-TB annually. On average, an estimated 9% of people with MDR-TB have extensively drug-resistant TB (XDR-TB) (Anonymous, 2014). Though tuberculosis mortality decreased considerably from 1990-2013, but the number of MDR-TB cases tripled from 2009-2013 (Anonymous, 2014). Recent studies report approximately 50,000 XDR (extensively drug resistant) cases of tuberculosis occur annually and are on the rise (Llamas-Gonzalez and Flores-Valdez, 2013). The XDR cases do not response to any treatment. These data alarm for the development of new drugs especially to fight MDR and XDR cases.
Paratuberculosis: Paratuberculosis or Johnes Disease (JD) is an economically devastating non-treatable chronic intestinal inflammatory condition of domestic ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP) and is characterized by un-thriftiness, reduced productivity, loss in body weight with or without diarrhea (Singh et al., 2014b). Economic losses due paratuberculosis in US dairy herds exceeds annually over $1.5 billion (Stabel, 1998). In US burden of disease increased from 21.6% infected dairy cattle herds in 1999-68.1% infected dairy herds in 2007 (Pillars et al., 2009). Therefore losses might have increased over the years. In India also burden of the disease has increased to a great extent in domestic ruminants over a period of last 28 years (Singh et al., 2014a). Besides paratuberculosis being economically important disease also has serious zoonotic concerns with humans Crohns disease (Singh et al., 2010). Milk has been considered as the major source of infection transmission to humans. Therefore, it is critical to control this infection in animals to secure animal productivity and restrict human exposure to this pathogen. Unfortunately, vaccines are not completely efficacious in controlling this disease and chemotherapy is not practiced due to risk to entrance of antibiotics in food chain through meat and milk. Therefore, plant derived medicines may prove safer option for controlling of this disease in animals.
PLANTS OF ANTI-MYCOBACTERIAL NATURE
Traditionally plant based medicines/plant extracts have been extensively used in different parts of the world for treating mycobacterial diseases. In recent past, efforts have been done to rediscover the traditional knowledge of plant based therapeutics used to treat mycobacterial diseases with plant species in different parts of the world including India. Surveys have been undertaken to collect this traditional knowledge. A questionnaire based interview of Traditional Medicine Practitioners (TMPs) of Mpigi and Butambala regions of Uganda reported 90 plant species used to cure tuberculosis traditionally (Bunalema et al., 2014). In this survey, Zanthoxylum leprieurii, Piptadeniastrum africanum, Albizia coriaria and Rubia cordifolia were most common species used to treat tuberculosis by TMPs (Bunalema et al., 2014). This survey also highlighted that leaves were the most commonly used plant part to cure the diseases. Survey done by Semenya and Maroyi (2013) showed that Bapedi tribes of Limpopo province of South Africa are dependent on traditional medicines for treating tuberculosis and are using about 21 plant species. Ethnobotanical survey in Eastern Cape province, South Africa reported about 30 plants used to treat tuberculosis by TMPs (Lawal et al., 2014). This survey reported that Clausena anisata, Haemanthus albiflos and Artemisia afra were most commonly used plant to tuberculosis treatment (Lawal et al., 2014). Reports from India also exit on traditional use of plants in mycobacterial infections. A survey of tribal population of Bankura district (West Bengal, India) reported use of plants like Andrographis paniculata, Azadirachta indica, Commelina benghalensis, Evolvulus alsinoides and Mussaenda frondosa for treatment of leprosy (Sinhababu and Banerjee, 2013). Another survey from South India, reported traditional use of Anacardium occidentale, Corallocarpus epigaeus, Indigofera aspalathoides and Trichosanthes lobata plants in treatment of leprosy (Kingston et al., 2009). Table 1 and 2 highlight surveys conducted in India and other parts of the world to list plants used to cure mycobacterial diseases in traditional medicine. Recently, there has been increased interest in testing of plants for anti-mycobacterial activity and a number of plants have been reported to have this activity. Table 3 summarizes the studies conducted in different plants of the world to identify plants with anti-mycobacterial activity.
|Table 1:||Ethno-medicine surveys for identification of plants used to treat mycobacterial diseases in India|
|Table 2:||Ethno-medicine surveys for identification of plants used to treat mycobacterial diseases in other parts of the world|
|Table 3:||Summary of the plants with potential anti-mycobacterial activity|
Arbitrary use of antibiotics has led to the evolution of Multi Drug Resistant (MDR) and extensively drug resistant (XDR) strains of mycobacteria, thereby making the control of these diseases even more difficult. Emergence of MDR and XDR strains has necessitated the urgent development of anti-mycobacterial drugs. Recent reports described that approximately 30% of MDR cases present treatment failures (Brigden et al., 2014). The MDR cases require two years of treatment with second-line drugs, which are more toxic and more expensive than first-line drugs (Zazueta-Beltran et al., 2011). Therefore, newer effective and safer drugs are urgently needed in order to shorten the therapy of MDR and XDR cases. Plants can served as excellent source of molecules active against MDR and XDR strains. Reports suggest that extracts from plants are active against MDR strains (Table 4).
PLANT METABOLITES WITH ANTI-MYCOBACTERIAL ACTIVITY
Natural products are of great interest since can provide novel structures for the drug discovery particularly effective as antimicrobial agents. As plants have high biodiversity therefore can serve as main source of natural compounds because of their rich metabolite content. Plant secondary metabolites have anti-mycobacterial properties. Alkaloids, flavonoids, phytosterols, saponins, tannins etc have been extracted from different plants with anti-mycobacterial activity. Table 5 lists important metabolites from plants with anti-mycobacterial activity.
|Table 4:||Plants having activity against MDR mycobacterial strains|
|MDR: Multi drug resistant|
|Table 5:||Active anti-tuberculosis molecules of plant origin|
CONCLUDING REMARKS AND FUTURE DIRECTIONS
Review of both traditional knowledge and testing of plants for anti-mycobacterial activity suggests that plants can serve as excellent source for anti-mycobacterial drugs. 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 fighting 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 identification of crude plant extracts with anti-mycobacterial properties and has not been extended to identification of bioactive plant metabolites. Therefore, an integrated approach of identification of plants with anti-mycobacterial activity followed by identification of bioactive molecule will speed up the research and development of plant derived drug molecules for mycobacterial infections.
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