Endemic Plants of Mauritius in Biomedicine: History
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Contributor:
Nawraj Rummun
,
Vidushi S. Neergheen

Resistance to the existing arsenal of therapeutic agents significantly impedes successful drug therapy. One approach to combat this burgeoning global crisis is to provide novel and more effective clinical agents. Terrestrial plants have long been exploited as a source of novel drug candidates. In this line, the endemic floral diversity of the Republic of Mauritius cannot be ignored. However, developing drugs from these plants is a multi-stepped, lengthy process that requires multistakeholder involvement from scientists, policymakers, and conservationists as well as the local community. 

  • drug resistance
  • Mauritius
  • endemic plants
  • anticancer
  • antimicrobial
  • bioactivity

1. Introduction

Even though the modern age is characterised by personalised medicine and the availability of monoclonal antibodies-based therapeutics in healthcare, failure in drug response is a frequent problem faced by clinicians [1][2]. A staggering 90% failure rate in cancer chemotherapy is reported [3]. Along a similar line, a study assessing the treatment outcome of initial antibiotic treatment in patients across five countries revealed an astounding 60% or higher antibiotic therapy failure rate for each country [4]. Similarly, the death toll due to the failure of drug regimens in treating life-threatening ailments is projected to rise annually [5][6]. Chemoresistance has been reported against almost all the anticancer agents in clinical use. About 90% of the 10 million cancer-related deaths in 2020 can be ascribed to drug resistance [7][8][9]. Likewise, nearly 5 million deaths in the year 2019 were attributed to antimicrobial drug resistance (AMR) [10]. The death toll due to AMR was projected to increase from an estimated 700,000 annual cases in 2016 to 10 million cases annually by the year 2050 [5].
The exacerbating threat that AMR poses has been acknowledged by international institutions such as the World Health Organisation (WHO), the United Nations (UN), and the (Group of Twenty) G20 leaders. Drug resistance to the available arsenal of pharmaceutical agents, coupled with their associated adverse drug reactions, further impedes the burgeoning burden of disease management. Furthermore, AMR considerably hinders the achievement of the UN sustainable development goals (SDGs), in particular SDG 3, which is “Good health and well-being” [11]. As such, a national action plan to tackle drug resistance, alleviate patient suffering, and curb the mortality rate has been adopted globally [12]. One approach to combatting drug resistance is to provide a perpetual addition of novel and innovative therapeutic agents to the existing armamentarium of clinical drugs [10][13]. This emphasises the need for ongoing research endeavours targeted toward identifying new drug candidates with the potential to be developed into clinically efficient therapeutic agents, preferably with an alternative mechanism of action.

1.1. Plants as a Source of Therapeutic Agents

The contribution of terrestrial plant-based natural products in the mitigation of human ailments, in particular oncologic and infectious diseases, is well established [14][15]. Aside from therapeutic agents, the health benefits of plants are also exploited as an important source of nutraceuticals and functional foods [16][17]. To adapt to their immediate environment and ensure their survival, plants have evolved to produce thousands to millions of structurally diverse and unique natural products that can also be exploited to human advantage in the development of life-saving drugs or herbal supplements [18]. Approximately 25% of the marketed therapeutic agents have their structural backbone originating from natural products [19]. For instance, digoxin (antidysrhythmic) from Digitalis latanata Ehrh (Plantaginaceae), artemisinin (antimalarial) from Artemisia annua (Asteraceae), metformin (antidiabetic) from Galega officinalis (Fabaceae), morphine (opioid analgesic) from Papaver somniferum (Papaveraceae), colchicine (uricosuric agent) from Colchicum autumnale (Colchicaceae), and cannabidiol (antiseizure) from Cannabis sativa (Cannabaceae) are notable examples of life-saving drugs derived from plants [20]. However, only a minute fraction of the global plant species have so far been evaluated for their therapeutic benefits [21]. Thus, novel compounds from biodiversity-rich tropical forests, particularly the untapped endemic floral species, still await to be explored.

1.2. Biouniqueness of Mauritius Flora

Endemic plants are species that grow in a restricted geographical region and have evolved apart from the rest of the world. Thus, endemic plants are a highly promising and fertile source of novel therapeutic agents [22]. The Mascarene archipelago, along with Madagascar island, is a biodiversity hotspot with exceptional floristic diversity and a high level of endemism [23]. The Mascarene Islands, consisting of Réunion, Mauritius, and Rodrigues Island, are located in the Indian Ocean, off the southeast coast of the African continent. Mauritius, a small-island developing state, has a documented floral diversity comprising 691 angiosperms. The latter harbours a high level of plant endemicity, with 39.5% of the recorded flowering plant taxa being strictly contained to the island and 61.2% being native to the Mascarenes archipelago only [24].
Along with being home to the highest number of single-island-endemic (SIE) plant species among the Mascarene Islands, Mauritius also has the highest level of threatened SIE (81.7%) [24]. Looking at the global distribution pattern of geographical regions with the highest recorded extinct plant species, Mauritius ranks in third place [25]. In less than four centuries, Mauritius has lost above 95% of its pristine forest canopy [26], therefore jeopardising the survival of most of the island’s indigenous plants. Nonetheless, the surviving endemic taxa are of inestimable value in the search for structurally unique chemotypes of pharmaceutical relevance.

2. The Readiness to Harness the Floristic Uniqueness of Mauritius in Biomedicine

2.1. Oncotherapeutic Potential of Mauritian-Endemic Plants

Twenty endemic plant leaf extracts’ cytotoxic effects have been reported against human cancer cell lines. For all the investigated extracts, the cell viability post extract treatment was assessed using either Alamar blue or MTT tetrazolium salt to measure the cellular metabolic activity and the reported IC50 value ranged from 5 µg/mL (for Psiadia terebinthina against Hs578T breast cancer cells) to 533 µg/mL (for Phyllantus phillyreifolius against HeLa cervical cancer cells). According to the United States National Cancer Institute criteria for cytotoxicity guidelines, crude extracts having an IC50 value below 20 µg/mL are considered potent candidates for further investigation regarding their anticancer potential, while extracts having an IC50 value above 100 µg/mL are considered inactive [27].
Leaves extracts of Acalypha integrifolia Willd (Euphorbiaceae), Eugenia tinifolia Lam. (Myrtaceace,) and Labourdonaisia glauca Bojer (Sapotaceae) have been reported to increase the intracellular level of 5′-adenosine monophosphate-activated kinase, thereby arresting oesophageal squamous cell carcinoma (KYSE-30) in the G2/M phase of the cell cycle. All three extracts had IC50 values below 10 µg/mL against KYSE-30 cells [28]. Syzygium coriaceum Bosser & J. Guého leaves extract inhibited the growth of human epithelial breast cancer (MDA-MB-231), liposarcoma (SW872), lung carcinoma (A549), and hepatocellular carcinoma (HepG2) cells, with an IC50 value ranging from 24 µg/mL to 53 µg/mL [29][30][31]. Likewise, Terminalia bentzoë leaves’ extract inhibited the growth of human ovarian carcinoma (OVCAR-4 and OVCAR-8), SW872, A549, and HepG2 cells, with IC50 values ranging from 23 µg/mL to 97 µg/mL, with HepG2 cells being the most susceptible cell line [32]. S. coriaceum was reported to trigger apoptosis in MDA-MB-231 cells via the downregulation of anti-apoptotic genes, notably BCL-2 and BIRC5 genes. Moreover, a decline in the gene expression of microtubule-associated protein 1 light chain 3 (LC3), beclin, and telomerase reverse transcriptase (TERT) was observed following S. coriaceum leaves’ extract treatment in MDA-MB-231 cells [29]. In the case of HepG2 cells, both S. coriaceum and T. bentzoë extracts treatment caused a surge in intracellular reactive oxygen species (ROS) level, inducing oxidative damage to DNA and provoking the collapse of the mitochondrial membrane potential (MMP), thereby arresting the cell in the G0/G1 phase of the replicative cycle [30][31][32]. 

2.2. Mauritian-Endemic Plants in Combatting Antimicrobial Resistance

The use of herbal formulations in the management of infectious diseases in Mauritius is well established [33]. The ethnomedicinal uses of Mauritian-endemic plants in the management of microbial diseases have been previously summarised [34]. An effort to compile the in vitro antimicrobial activities of indigenous plants, including endemic species, published up to 2019 was made by Suroowan et al. [35]. The inference from the scientific literature published by several independent research groups revealed that thirty-six Mauritian-endemic plant species, when applied in the form of leaves’ extracts, imposed in vitro growth-inhibitory activity against a broad spectrum of microbial strains, including both bacteria and fungi.
Six leading deadly bacteria, notably Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, accounted for 73.4% of antimicrobial resistance-related death globally for the year 2019, with drug-resistant strains of E. coli claiming the highest number of death [10]. The lethality of these bacteria was also recognised by the WHO, and they are earmarked as high-priority pathogens for developing novel antibiotics capable of killing these bacteria [36]. The following literature, therefore, focuses on endemic species having reported antimicrobial activities against these six drug-resistant pathogens.

2.3. Key Challenges

Attempts to discover potent bioactive extracts from the island’s indigenous floral diversity, with the ambition to establish potential clinical concoctions or purified molecules, have been the epicentre of investigation for various research groups in the past decades. In the search for promising drug candidates, some investigators have allowed their research work to be guided by the medicinal uses of endemic plants, intending to elucidate the active ingredients and validate their purported therapeutic claims [37][38][39][40][41][42][43][44][45][46][47][48]. Meanwhile other scientists have randomly screened the unexplored unique floral reserve, aiming to evaluate the health benefits of these endangered plant species before their permanent loss due to extinction [29][30][31][49][50]. Yet, a pre-clinical drug candidate budding from the endemic resources of Mauritius is beyond the horizon. Drug research in Mauritius is associated with numerous challenges and limitations. 

The crude herbal extracts or essential oils tested are comprised of a mixture of structurally diverse molecules, making it difficult to successfully differentiate the bioactive components from the pool of inactive molecules [51]. Identifying principal bioactive components present in the crude extracts and their purification is paramount to establishing their molecular mode of action and their pharmacokinetic and toxicity profile. Only three studies have attempted to delineate the bioactive compounds through bioassay-guided fractionation [30][32][46].

From a mechanistic point of view, limited insight is provided regarding the mode of action of the extracts. Promising anticancer extracts are reported to induce cell cycle arrest in malignant cells. However, the molecular cascade of events is yet to be elucidated. Likewise, the antibacterial mechanism of action of the two Psaidia species is restricted to their ability to modulate the efflux pump in the organism. More rigorous investigation of the targeted signalling pathways, gene modulations, and alterations in the cellular microenvironment is prescribed.

This entry is adapted from the peer-reviewed paper 10.3390/ddc2020018

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