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Canadian Traditionally Used Medicinal Plants: Can They Play A Role in Antituberculosis Drug Development?

2013; Future Science Ltd; Volume: 5; Issue: 8 Linguagem: Inglês

10.4155/fmc.13.64

1756-8927

Christopher A. Gray, John A. Johnson, Duncan Webster,

Fungal Biology and Applications

Future Medicinal ChemistryVol. 5, No. 8 EditorialFree AccessCanadian traditionally used medicinal plants: can they play a role in antituberculosis drug development?Christopher A Gray, John A Johnson & Duncan WebsterChristopher A Gray* Author for correspondenceDepartment of Chemistry, University of New Brunswick, Saint John, New Brunswick, Canada E2L 4L5 and Department of Biology, University of New Brunswick, Saint John, New Brunswick, Canada E2L 4L5. , John A JohnsonDepartment of Biology, University of New Brunswick, Saint John, New Brunswick, Canada E2L 4L5 & Duncan WebsterDivision of Infectious Diseases, Department of Medicine, Saint John Regional Hospital, Saint John, New Brunswick, Canada E2L 4L2Published Online:20 May 2013https://doi.org/10.4155/fmc.13.64AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: antimycobacterial agentsethnopharmacologyfungal endophytesmedicinal plantsMycobacterium tuberculosisnatural productstuberculosisThe highly pathogenic organism Mycobacterium tuberculosis has plagued human civilization for millennia. Driven by poverty, malnutrition and overcrowding, epidemics of tuberculosis (TB) with high rates of morbidity and mortality continue to be observed around the globe [1]. When used in combination, the anti-TB therapeutics developed in the mid-20th century were initially effective and, as rates of active disease fell in the developing world, funding for continued research and development of new TB therapeutics dried up. However, a resurgence of TB fanned by the HIV pandemic and rising rates of drug resistance led to TB being declared a global emergency in 1993. The present sobering reality is that while the standard first-line drug regimen has remained essentially unchanged for a half century, never before has TB been so prevalent [1].The response to this global threat has been complicated by increasing rates of multidrug-resistant and extensively drug-resistant (XDR) TB. Inadequate drug regimens and poor adherence to protracted therapeutic schedules have contributed to the emergence of these drug-resistant strains, which are associated with high transmission and mortality rates. Alarmingly, XDR strains with augmented resistance, described as extremely drug-resistant and totally drug-resistant TB, have also recently been observed. While there is currently no official definition for strains with therapeutic resistance beyond XDR TB, it is clear that the prognosis for patients infected with them is bleak and treatment options are severely limited.In order to address this global crisis, the establishment of new therapeutics is crucial. Increased drug discovery and development efforts over the last decade have resulted in clinical trials of a limited number of new drugs or drug combinations [101]. Of these, bedaquiline (TMC207) is the first medication with a novel mechanism of action against TB to receive US FDA approval in more than 40 years [2]. Delamanid (OPC-67683) has also demonstrated promise against drug-resistant M. tuberculosis as a mycolic acid synthesis inhibitor [3]. Despite these achievements, there remains an urgent need to identify new antimycobacterial agents that are structurally or functionally novel.Historically, natural product research has provided a wealth of small molecules, driving drug discovery and development, and maintaining the pharmaceutical industry. Although there was a significant shift toward combinatorial and rational approaches in the late-20th century, the failure of these strategies to provide sufficient chemical diversity emphasized the importance of screening biodiversity for new chemical entities with novel biological activities [4]. Natural product research is re-emerging as a paramount source of drug leads and continues to be a major contributor to drug discovery and development.Concurrent with the renaissance of natural product chemistry, is increased interest in ethnopharmacology and use of traditional medicines [5]. The aboriginal peoples of Canada have a rich ethnobotanical history and have used plants extensively as therapeutics [6]. Surprisingly, there have been few phytochemical studies focusing on Canadian medicinal plants, despite the fact that screening studies conducted in the 1990s demonstrated a high degree of correlation between therapeutic uses and observed biological activity of plants [7–11]. Archeological and ancient DNA data demonstrate that TB has been endemic in the Americas for at least 3500 years [12,13], therefore, it is not surprising that some plants were used to treat TB or, in the absence of modern diagnostics, illness consistent with the active disease. Indeed, extracts of some of these plants exhibit significant antimycobacterial activity [11] and work that we have conducted on only a fraction of the Canadian medicinal plants that have been used to treat TB has already provided lead structures that require further investigation.This work also presents an opportunity to gain further understanding of certain traditional medicines, which may be important for additional reasons. It has been recognized that an integral part of healing the wounds that persist within Aboriginal communities following centuries of injustice and multi-generational trauma involves revitalization through lifting up age-old traditions of the Canadian indigenous peoples [14]. When knowledge of Canadian traditional medicines is received by scientists in a respectful manner and used in good faith without expropriation or exploitation, many stand to gain from a number of different perspectives. The benefits of this type of partnership have been demonstrated by a Canadian Institutes for Health Research funded collaborative project addressing Type II diabetes where researchers successfully partnered with the Cree of Eeyou Istchee in Quebec [102]. Likewise, investigation of medicinal plants with antimycobacterial activity may stand to assist local First Nations communities on cultural and spiritual levels, while also benefiting the global community in terms of requisite novel anti-TB agents.Interestingly, it is not only medicinal plants that are a source of chemical diversity: endophytic assemblages of microorganisms that they sustain may hold the most promise for drug discovery. Fungal endophytes reside inside plants without causing disease [15], and a growing body of research indicates that endophytes can produce bioactive compounds. A recent review exposed the paucity of our knowledge regarding the endophytes of medicinal plants, highlighting the need for research in this area [16]. Indeed, our preliminary work with 96 endophytes isolated from 12 Canadian medicinal plants demonstrates that endophytes produce compounds that inhibit the growth of M. tuberculosis and underscores their potential to provide novel antimycobacterial compounds. Our results pertain only to endophytes isolated from leaves of medicinal plants. However, as endophytes have been isolated from essentially all plant tissues and are known to have varying degrees of organ or tissue specificity [17], future work should be expanded to include all parts of medicinal plants. We have also determined that endophytes grown using co-culture techniques have potential to produce additional or different compounds than those grown in monoculture. The ability to induce cryptic endophyte biosynthetic gene clusters into action creates the possibility of isolating an increased array of antimycobacterial compounds and presents additional dimensions to the study of medicinal plants.The opportunities for drug discovery provided through medicinal plants are extensive and multifaceted. However, from a Canadian perspective, many challenges persist and a great deal remains to be accomplished if the potential of this resource is to be realized. The lack of phytochemical work focused on Canadian medicinal plants represents a chasm in global ethnopharmacological knowledge. This must be addressed, but will require the development of working relationships and partnerships with Canadian Aboriginal groups that include memorandums of understanding to ensure the protection of Aboriginal community interests, and clearly identifies and recognizes their role in the generation of any and all intellectual property that may be generated. There is also a need to vastly increase our fundamental knowledge of endophyte biology at all levels, from their molecular biology to their ecology; we simply do not know the role that these organisms play in the life cycles of higher plants, nor do we know the scope of their importance. In the face of declining global markets for timber, pulp and paper products, the Canadian Forestry Industry is having to transform, diversify and develop innovative non-traditional products [18]. Companies involved in Canada's forest sector should be encouraged to embrace medicinal plants as alternative, value-added products and consider the natural health market not only as a potential area for expansion but also as an opportunity to develop new partnerships with Aboriginal communities. Finally, if big pharmaceutical companies are not willing to commit resources to anti-TB drug discovery, funding must be put in place for academic and government laboratories to fill this void. In Canada, natural product drug discovery overlaps the mandates of federal agencies that fund natural (Natural Sciences and Engineering Research Council) and health (Canadian Institutes for Health Research) sciences. While this provides significant opportunities for natural products research, in the face of significant reductions to granting agency budgets, it can also make the acquisition of funding problematic. With current forecasts predicting that broadscale antimicrobial ineffectiveness is imminent, the discovery of new anti-infective agents should be identified as a strategic research priority by the Canadian Government and resources put in place to facilitate research in this area.Given the seriousness of TB globally, no potential source of new antimycobacterial agents should remain uninvestigated. The track-record of natural products as a source of therapeutic agents is unsurpassed and natural products research should never have been neglected as an avenue for drug discovery. Without question, TB has had a devastating impact on the indigenous peoples of the Americas and high rates of TB persist, driven by the social determinants of this infectious disease. In the face of this plague, Aboriginal communities have been able to selectively identify traditional medicines with activity against this pathogen. In the global fight against TB, momentum for drug discovery has only recently been generated; Canadian traditionally used medicinal plants and the endophytic fungi residing in their tissues can certainly play a role in maintaining this momentum.Financial & competing interests disclosureThe authors would like to acknowledge the following sources of research funding: Horizon Health Network, the Natural Sciences and Engineering Research Council of Canada, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation and the University of New Brunswick. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.References1 WHO. Global Tuberculosis Report. WHO press, Geneva, Switzerland 1–272 (2012).Google Scholar2 Voelker R. MDR-TB has new drug foe after fast-track approval. JAMA309(5),430–430 (2013).Crossref, Medline, Google Scholar3 Gler MT, Skripconoka V, Sanchez-Garavito E et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N. Engl. J. Med.366(23),2151–2160 (2012).Crossref, Medline, CAS, Google Scholar4 Danishefsky S. On the potential of natural products in the discovery of pharma leads: a case for reassessment. Nat. Prod. Rep.27(8),1114–1116 (2010).Crossref, Medline, CAS, Google Scholar5 Cordell GA, Colvard MD. 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CIHR Team in Aboriginal Antidiabetic Medicines. www.taam-emaad.umontreal.ca (Accessed 5 March 2013)Google ScholarFiguresReferencesRelatedDetailsCited ByChanges of Anti-tuberculosis Herbs Formula During Past Three Decades in Contrast to Ancient Ones9 July 2020 | Chinese Journal of Integrative Medicine, Vol. 27, No. 5Plant‐based Food Products for Antimycobacterial Therapy30 April 2020 | eFood, Vol. 1, No. 3Antimycobacterial Natural Products from Endophytes of the Medicinal Plant Aralia nudicaulis1 October 2015 | Natural Product Communications, Vol. 10, No. 10Isolation of Phomopsolide A and 6(E)-Phomopsolide A as Antimycobacterial Products from an Unidentified Endophyte of the Canadian Medicinal Plant Heracleum maximum1 October 2015 | Natural Product Communications, Vol. 10, No. 10Chinese herbal medicine as adjuvant treatment to chemotherapy for multidrug-resistant tuberculosis (MDR-TB): A systematic review of randomised clinical trialsTuberculosis, Vol. 95, No. 4Optimisation of the Microplate Resazurin Assay for Screening and Bioassay-guided Fractionation of Phytochemical Extracts against Mycobacterium tuberculosis14 April 2014 | Phytochemical Analysis, Vol. 25, No. 5 Vol. 5, No. 8 Follow us on social media for the latest updates Metrics History Published online 20 May 2013 Published in print May 2013 Information© Future Science LtdKeywordsantimycobacterial agentsethnopharmacologyfungal endophytesmedicinal plantsMycobacterium tuberculosisnatural productstuberculosisFinancial & competing interests disclosureThe authors would like to acknowledge the following sources of research funding: Horizon Health Network, the Natural Sciences and Engineering Research Council of Canada, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation and the University of New Brunswick. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.PDF download