Therapeutic potentials of endophytes for healthcare sustainability

ABSTRACT Morbidity and mortality rates are on the upward trajectory globally, probably due to lack of effective treatments and poor healthcare. Most effective drugs are, however, characterized by serious side effects upon long usage. It is, therefore, imperative to explore natural sources for efficient therapeutics with little or no side effects. This paper outlines the therapeutic potentials of endophytes using published articles on endophytes in both Web of Science (WoS) and Scopus (1990–2020). Scientific evidences discussed in this review suggest endophytic microbes as reservoirs of novel bioactive compounds belonging to the following classes alkaloid, xanthones, methoxyphenols, depsipeptide, bicyclic lactones, depsidoenes, butenolides, maleimide-bearing compounds, ergosterol, spirobisnaphthalenes, benzopyran derivatives, isofuranonaphthalenone, butyrolactones, diketopiperazine, sesquiterpenoids, cytochalasin-related compounds, pestalols and cyclic pentapeptides. The identified compounds are characterized by promising therapeutic potentials such as antioxidant, anti-inflammatory, antimicrobial, anticancer, antidiabetic, antiviral, neuroprotective, and hepatoprotective properties, which are significant to healthy living and sustainable healthcare. This review further discusses the emerging potentials of endophytes in the production of antibiofilm, anti-multiresistant Staphylococcus aureus (anti-MRSA) and lipase inhibitors (LIs). The prospective applications of endophytes in the development of anti-COVID-19 medications and therapeutics for the management of neglected tropical diseases (NTDs) are also advocated in this review. The therapeutic potentials of endophytes, if properly harnessed, would in no small measure contribute to good health, which is an integral part of the sustainable development goals (SDGs) of the United Nations (UN).


Introduction
Endophytes are microbes which grow inside plant tissues [1] and exhibit great biodiversity in nature based on endophyte-plant interactions, endophytic behavior, endophyte-plant association, endolichen-infection, endophytic compartment, endophyte infection, endophytic colonization, endophytic bacteria-algae interactions/association and endophytic competence among others [2]. A text mining of endophytic microorganisms from collections of previous studies revealed diversity of endophytes across bacterial, fungal, yeast, algae and actinomycetes groups.
Endophytic microbes are characterized by the capability to produce varieties of secondary metabolites [3], which have shown significant pharmaceutical potentials such as antioxidant, anticancer, immunomodulatory, antiviral,

Identification and mining of endophyte resource
The study mined public available endophyterelated research articles in the WoS and Scopus databases from 1990 to 2020 (Tuesday, 07 July 2020, 22:00:05, GMT +1) following the guideline of the 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses: PRISMA' [20]. The database mining was achieved via the term 'endophyt*', which optimally retrieved variant indexes (e.g., endophytes, endophytes and endophytic) as title-specific search. The investigation final database was composed chiefly research articles but was devoided of pre-articles and post-publication synthesis such as note, correction addition, meeting abstract, correction, news item, retracted publication, proceedings paper, editorial material, data paper, biographical item, review, letter, book, retraction, book chapter, etc.
( Figure 1). The integrity of applied search algorithm was manually validated by assessing the top 20 articles for specificity and efficiency. The articles metadata were all downloaded either as tab-delimited (Win, UTF-8) or comma separated (CSV Excel) file for further processing [].

De-duplication of endophyte-documents and subject classification
The metadata obtained from the two databases in the previous section were hybridized and deduplicated in a python programming environment using ScientoPy package following the protocol of Ruiz-Rosero et al. (2019) [21]. Topical classification of the therapeutic potentials of endophytes were based on average growth rate or trends of authors-keywords in the review database as described by equation 1:  The topics considered include antioxidant  potential (antioxidant compound, antioxidant  potential, antioxidant properties, antioxidant  activities); neuroprotective property (antiacetylcholinesterase, antiacetylcholinesterase,  acetylcholinesterase inhibition, cholinesterase  inhibition, anti-AChE activities, antibutyrylcholinesterase; anti-BChE activities, butyrylcholinesterase inhibition); anticancer potential (anticancer, antimitotic, antitumoral, antineoplastic, cancer inhibition, antitumor, antiproliferative, antimetastatic, antimutagenic activities, antiangiogenesis); anti-inflammatory activities; antimalarial (antimalarial, antiplasmodial); antiprotozoal and anti-parasitic (antileishmanial, leishmanicidal; antitrypanosomial,, trypanocidal, schistosomicidal, anti-filarial); antidiabetic (glucosidase inhibition, alpha amylase inhibition); antiviral (anti-hcv, antihepatitis C Virus, anti-influenza activities, HIV-1 integrase inhibitory, anti-respiratory syncytial virus); hepatoprotective property (liver protective); and the emerging potentials (antibiofilm, anti-MRSA, lipase inhibition). This review is categorized under the following broad themes: anticancer property, anti-inflammatory, antimalarial activity, antidiabetic property, antioxidant activity, hepatoprotective activity, neuroprotective activity, antiviral property, and emerging potentials as discussed in the succeeding sections. Although, there are many documents related to the outlined topics, this review is limited to the most relevant recent studies in the review database as identified by equation 1.

Therapeutic potentials of endophytes
This section discusses the scientific evidences that suggest endophytes as reservoirs of novel bioactive compounds with promising therapeutic potentials. Copious natural compounds have been isolated and purified from different endophytic microbes over the years. The therapeutic potentials of such compounds and the respective sources are summarized in Table 1.

Anticancer property
Identification of studies on 'anticancer property of endophytes' as described by equation 1 returned 287 articles for journals published between 1990 and 2020, out of which 26% were published between 2018 and 2020, implying that the anticancer efficacy of endophytederived extracts and compounds are still of research interest. The continued interest in cancer research is not surprising, as cancer is one of the leading causes of death globally.
Cancer research efforts have undoubtedly, yielded positive results as a wide range of natural anticancer compounds have been isolated from different sources including endophytes. Taxol, a popular chemotherapy drug used in cancer treatments, has been isolated from a number of endophytes hosted by plants belonging to Taxus and Taxodium genera [22][23][24]. Other taxol-producing endophytic fungi include Pestalotiopsis versicolor and Pestalotiopsis neglecta [25]. The toxic effect of taxol on various cancer cell lines, including BT220, HEPG2, HLK 210, MCF7, Int 407, HI 16 and HL 251, have been reported [26,27]. Deoxypodophyllotoxin, another anticancer agent, has been isolated and purified from an endophytic Aspergillus strain [28]. Deoxypodophyllotoxin is used as a pro-drug in the management of cancer. Ding et al. [29] isolated a cytotoxic alkaloid, chaetoglobosin U from an endophytic fungus belonging to Chaetomium genus. The authors confirmed that the bioactive compound 'chaetoglobosin U' had toxic effect on 'human nasopharyngeal epidermoid tumor KB cell line' with the inhibitory rate correlating with that of the positive control [5-fluorouracil) [30]. A different study by 99, reported the isolation of falcarinol from a Paecilomyces species hosted by Panax ginseng. It is noteworthy that Paecilomyces falcarinol exhibited remarkable in vitro antitumor effect against different cell lines [30]. Also, anthracenedione derivatives separated from endophytic fungal strains belonging to Guignardia and Halorosellinia genera inhibited proliferation of KB and KBv200 cells via apoptotic-related mechanisms [31].
Furthermore, Taechowisan et al. [32] reported the anticancer activity of arylcoumarins isolated from an endophytic bacterial strain,

Streptomyces aureofaciens
CMUAc130. Interestingly, the bioactive compound inhibited the growth of 'Lewis lung carcinoma (LLC)' in experimental mice through apoptotic mechanism related to reduction in BCL-2 and overexpression of BAX [32]. The cytotoxic effects of extracts from the following endophytes: Fomitopsis sp. P. Karst, Alternaria alternate (Fr.) Keissl and Phomposis sp. against breast and colon cancer cell lines have been documented. The bioactive compound isolated from the Phomanolide (-)-6-methoxymellein [16] extracts, camptothecine (a quinoline alkaloid), exhibited its anticancer activity through inhibition of topoisomerase I. Remarkably, some compounds derived from camptothecine are already being used as therapeutics for different forms of cancers [33]. Camptothecine and its derivatives are believed to account for over 30% marketed anti-cancer drugs [34].
Alternaria alternate, obtained from Capsicum annum, has shown dexterity for the production of capsaicin and alternariol-10-methyl ether, which showed cytotoxicity against different cancer cells such as HL-60 cells through initiation of apoptosis [35].
Endophytes are also sources of the anticancer enzyme, asparaginase. Studies have shown that asparaginase from Colletotrichum sp. E5T9 effectively inhibited the survival rate of CaCo2 (colon adenocarcinoma) and HepG2 (hepatocyte carcinoma) cells [36,37]. However, beauvericin, a cyclic peptide purified from Fusarium sp. (No. DZ27) has been reported to inhibit KB and KBv200 cells growth by induction of 'apoptosis' via amelioration of oxidative stress, release of cytochrome c, upregulation of 'caspase-9 and −3, cleavage of poly (ADP-ribose) polymerase (PARP)' and failure of mitochondrial membrane potential [38]. Also, sclerotiorin obtained from Cephalotheca faveolate has been shown to stop the proliferation of colon cancer (HCT-116) cells through increased production of BAX, lowered production of BCL-2 and consequently, elevated the amount of cleaved caspase-3, which caused apoptosis of cancer cell lines [39].
Other compounds from endophytes that exhibited cytotoxic activities against various cancer cells include '1,5-dihydroxy-3-hydroxyethyl-6-methoxycarbonylxanthone and 1-hydroxy-3-hydroxyethyl-8-ethoxycarbonylxanthone', which were isolated from Phomopsis sp [40]. and myrotheciumones A and B from Myrothecium roridum inhabiting Ajuga decumbens [41]. Moreover, a peptide from Capsicum annuum endophyte, EML-CAP3, was reported to show strong antiangiogenic activity in varied experimental conditions, through various molecular mechanisms [42]. The stimulation of angiogenesis is an important step in tumor development. Thus, effective blockage of angiogenesis is believed to be a reasonable approach in the treatment of cancer. Furthermore, phenolic-rich extract from an endophytic fungus, Aspergillus nomius disrupted the growth of human breast cancer cell and caused apoptosis [43]. Most of the aforementioned anticancer bioactive compounds from endophytes are alkaloids, xanthones, phenolics, depsipeptides and lactones among others.

Anti-inflammatory activity
Of the 88 articles returned by equation 1 on the anti-inflammatory property of endophytes, 60% were published between 2018 and 2020, meaning that the anti-inflammatory capacity of extracts and compounds of endophytic origin is currently attracting research interest. A specific example of such studies reported that compounds isolated from Phomopsis sp. SYSUQYP-23, including farinomalein H, displayed high modulatory effects on nitric oxide (NO) generation in 'lipopolysaccharides (LPS)induced RAW 264.7 cells' [44]. The antiinflammatory potential of chlamydosterols A, an ergosterol separated from Fusarium chlamydosporum isolated from the foliage of Anvillea garcinii (Asteraceae) has been reported. Chlamydosterols was reported to have shown comparable 5-lipoxygenase inhibitory activity with the standard anti-inflammatory drug, 'indomethacin' [45]. More so, spirobisnaphthalenes from Edenia gomezpompae, as well as benzopyran derivatives from Penicillium citrinum QJF-22 exhibited anti-inflammatory activities as evidenced by their potent inhibition of the generation of 'NO in LPS-induced RAW 264.7' macrophages [19,46]. Furthermore, boremexins A, B, C and D obtained from Boeremia exigua, have displayed anti-inflammatory activity toward NO generation in LPS-induced RAW264.7 macrophages [47]. Also, libertellenone M from Phomopsis sp. S12 exhibited anti-inflammatory capacity in experimental models. Libertellenone M downregulated proinflammatory cytokine in LPS-treated macrophages, cleavage of pro-caspase 1 and repressed NF-κB nuclear translocation in macrophages [14]. Just like indomethacin, 1, 4-naphthoquinone derivatives, obtained from an endophytic Talaromyces species, significantly inhibited 'LPS-induced NO production in RAW 264.7 cell lines', as evidenced by inhibition of cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS) and (COX-2) mRNA expressions, as well as reduction of the levels of proinflammatory factors interleukin-1β, IL-6, and TNF-α [48].
Other compounds of endophytic sources, which have displayed anti-inflammatory activity in vitro include cowabenzophenone A from Aspergillus terreus residing in Bruguiera gymnorrhyza, desmethyldichlorodiaportintone from an Ascomycota species hosted by Pluchea indica [49,50] and terrusnolide A, B, C, and D isolated from Aspergillus species hosted by Tripterygium wilfordii [51]. Others include corynesidone A, C, and D and corynether A isolated from Corynespora cassicola, which caused concentration-dependent reduction of 'LPS-induced TNFα and iNO in RAW264.7' cells [52]. It is worthy of note that majority of the listed (Table 1) endophytic bioactive compounds with antiinflammatory activities belong to the following classes: depsidoenes, butenolides, maleimidebearing compounds, ergosterol, spirobisnaphthalenes, depsidones and benzopyran derivatives.

Antimalarial activity
From the identification of studies on the antimalarial activity of endophytes by equation 1, 30 publications were retrieved with 'antimalaria' as the key word while seven articles were retrieved with 'antiplasmodia' as the key word.
Of the thirty publications on antimalaria, 20% were published between 2018 and 2020 while for the seven studies published on antiplasmodial activity, 33% were published between 2018 and 2020. From these studies, various endophytic isolates were reported to exhibit antiplasmodial activities [53-57]. A specific example of antiplasmodial compounds include the cyclodepsipeptide, fusaripeptide A, isolated from an endophytic fungus inhabiting Mentha longifolia. Fusaripeptide A exhibited remarkable anti-Plasmodium falciparum (D6 clone) activity [15]. In another study, the compound, '3-(2-Hydroxypropyl) benzene-1,2-diol' purified from an endophytic fungal strain was reported to have displayed anti-plasmodial activity against the multidrug-resistant K1 clone, using dihydroartemisinin as the standard drug [ [62]. This review suggests that members of the isofuranonaphthalenones, butyrolactones, diketopiperazine and cyclodepsipeptides may be promising candidates for development of anti-malarial drugs.

Antidiabetic property
The antidiabetic activity of a number of endophytic extracts and compounds have been reported by various studies [63][64][65]. The search on the antidiabetic activity of endophytes using 'antidiabetic' as the key word in equation 1 returned 33 items, 39% of which, were published between 2018 and 2020. 'Glucosidase inhibition' and 'amylase inhibition' together returned 8 items, of which, 50% were published between 2018 and 2020. From some of these studies, the endophytic Aspergillus awamori isolated from Acacia nilotica was reported with the ability to produce an uncharacterized peptide with alpha glucosidase and alpha amylase inhibitory activities [66]. The extract and the compounds: '(S)-(+)-2-cis-4-trans-abscisic acid, 7ʹhydroxy-abscisic acid and 4-des-hydroxyl altersolanol A' obtained from Nigrospora oryzae hosted by Combretum dolichopetalum were reported to exhibit ability to reduce the fasting blood sugar of alloxan-induced diabetic mice [67]. Also, peniisocoumarins C, G and I, obtained from Penicillium commune QQF-3, have exhibited strong inhibitory activity against alphaglucosidase [68].

Antioxidant activity
The antioxidant activity of endophytes has attracted much research interest as database search using 'antioxidant' as the key word in equation 1 returned 462 items, of which, 41% were published between 2018 and 2020. Scientific findings revealed that endophytes are potential sources of novel natural antioxidant compounds [69,70]. Specific example includes the methanolic extract of Xylaria sp. YX-28, an endophyte inhabiting Ginkgo biloba, which exhibited notable antioxidant activity in β-carotene-linoleic acid and 2,2diphenyl-l-picrylhydrazyl (DPPH) antioxidant model systems [71]. Ethyl acetate extract of Eugenia jambolana endophyte exhibited significant antioxidant activities as revealed by DPPH and hydrogen peroxide scavenging abilities, as well as ferric reducing power [72]. The antioxidant activity of graphislactone A from endophytic Cephalosporium sp. IFB-E001, isolated from Trachelospermum jasminoides, has been established using DPPH, hydroxyl radical, linoleic acid and human lowdensity lipoprotein (LDL) experimental models [73]. More so, the antioxidant activity of the ethanolic extract (majorly containing luteolin) from the endophytic Aspergillus fumigates of Cajanus cajan has been reported. The extract displayed potent antioxidant ability as evaluated by OH radical scavenging, DPPH, reducing power and xanthine oxidase inhibitory and lipid peroxidation assays. The extract also protected DNA from oxidative damage and significantly increased the expression of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) activities in HepG2 cells [74]. Likewise, flavipin, purified from Chaetomium globosum CDW7, has also been reported to possess antioxidant activities and its level determined the antioxidant activity of the crude extracts obtained from the endophyte [75]. Adenosine, adenine and 2 'deoxyadenosine from a Penicillium species hosted by Ginkgo biloba have also exhibited potent antioxidant activities [76].

Hepatoprotective activity
Of the 5 research items published on the hepatoprotective potentials of endophytes between 1990 and 2020, 3 (60%) were published between 2018 and 2020. Examples from these studies include 'Ocimum sanctum Linn. endophytic fungal fraction', which at 200 mg/kg p. o., significantly upturned the effects of carbon tetrachloride (CCl 4 )-induced hepatotoxicity, by normalization of serum aspartate transaminases (AST), alanine transaminases (ALT), alkaline phosphatase (ALP) and hepatic damage biomarkers relative to CCl 4treated group. Restoration of altered lipid peroxidation, glutathione (GSH) and CAT by the fungal extract suggest that the hepatoprotective effect is possibly via the antioxidant action of the extract [77]. The ethyl acetate extract of Achaetomium sp. hosted by Euphorbia hirta has been reported to protect against CCl 4 induced toxicity in HepG2 cells as evidenced by 72.13% of cell viability at a concentration of 150 mg/mL compared to 93.26% cell viability reported for the standard, silymarin [78].
The protective effects of ethyl acetate and n-butanol fractions obtained from Preussia sp. PPV3.6 (APLF-2), an endophyte isolated from Andrographis paniculata leaves, on paracetamol-and ethanol-induced hepatotoxicity have also been reported as evidenced by their capacities to alter serum hepatic damage biomarkers, total cholesterol and triglycerides relative to paracetamol-and ethanol-treated groups. The extracts also restored lipid peroxidation, SOD and CAT levels in treated animals [79]. The hepatoprotective properties of two fungal endophytes (APLF-1 and APLF-2) isolated from Andrographis paniculata leaves against CCl 4induced hepatotoxicity have also been reported [79].
Furthermore, the ethyl acetate extract and some of the compounds isolated from the endophytic fungus, Alternaria alternate, exhibited potential neuroprotective activities in glutamate induced-PC12 injured cells [82]. Also, cytochalasin-related compounds isolated from the endophytes of Chaetomiun globosum WQ and Phomopsis sp. IFB-E060 have been reported to exhibit neuroprotective effect by inhibiting H 2 O 2 /MPP + -induced damage in PC12 cells, increasing cell viability and decreasing the amount of lactate dehydrogenase released from the damaged cells [17].

Antiviral property
The search of the selected databases on the antiviral potentials of endophytes with 'antiviral' as key word in equation 1 returned thirtysix studies (22% of which, were published between 2018 and 2020); 'anti-HIV' as key word returned eight studies (only one of which, was published between 2018 and 2020) while 'anti-HCV' (anti-hepatitis C virus) and 'anti-influenza activity' returned four studies, 2 of which, were published between 2018 and 2020.
On anti-influenza potentials of endophytic products, 6-O-demethyl-4-dehydroxyaltersolanol A (an hydroanthraquinone derivative) and other compounds isolated from the fermentation product of Nigrospora sp. YE3033, an endophytic fungus inhabiting Aconitum carmichaeli were reported to exhibit retarding effects on influenza viral strains including A/Puerto Rico/ 8/34 (H1N1), indicating the potential of these compounds as anti-influenza A virus agents [83]. Also, phomanolide (-)-6-methoxymellein, isolated from the fermentation culture of Phoma sp. from Aconitum vilmorinianum roots, has been reported to show antiviral activities against the same strain of influenza A virus [16]. Similarly, pestalols A, B, C, D, and E and other compounds purified from Pestalotiopsis sp. AcBC2, residing in Aegiceras corniculatum, exhibited inhibitory effects against Influenza A virus (H3N2) and Swine Flu (H1N1) [84]. Pullularin A from Pullularia sp. BCC 861 was reported to exhibit among other activities, antiherpes simplex virus type-1 activity [62] while the extract of Chaetomium globosum JN711454 was reported to exhibit activity against herpes simplex virus type −2 [85]. Furthermore, the sesquiterpenoids, brasilamides B, C, and D, isolated from the fermentation broth of the endophytic fungus, Paraconiothyrium brasiliense Verkley inhibited 'HIV-1 replication' in C8166 cells [86]. Malformin A1, a peptide obtained from Aspergillus tubingensis FJBJ11, an endophytic fungus of Brucea javanica (L.), displayed effective inhibitory activity against the infection and multiplication of the tobacco mosaic virus, indicating the potentials of endophytic products as new viricide [46].

Emerging potentials of endophytes
In this section, we highlight the emerging potentials of endophytes in the production of antibiofilm metabolites and bioactive compounds with inhibitory effects on multi-resistant Staphylococcus aureus (MRSA) and lipase. These traits are regarded as emerging in endophytes because majority of these attributes have only been reported recently with very limited studies.

Antibiofilm potential
Biofilm formation is one the various means by which bacteria evade antibiotics, disinfectants and biocides. Biofilms constitute a menace in infection treatment, giving rise to antibiotic resistant pathogens as well as chlorine-resistant bacteria in water and wastewater treatment plants and distribution systems. Table 2 lists emerging applications of antibiofilm potentials of endophytic microbes and their host organisms. Antibiofilm potentials of endophytic strains have possible applications across a wide range of biotechnological sectors include antibiofilm therapeutics/biomedical application (Rajesh and Ravishankar 2014) [87,88,89], antibiofouling/environmental application [90], application in management of diabetes [91], hydrocarbons cleaning [92], oral and dental antibiofilm therapeutics application [93], and agricultural/environmental applications [94].

Production of anti-MRSA compounds
Even though, S. aureus is part of our natural microbiota, it occasionally poses a threat to human lives as a pathogen and 'a leading cause of hospital and community-acquired infections' [96]. S. aureus is one of the most stubborn pathogenic bacteria, perhaps, due to its multi-drug resistance phenotypic traits, which obviously frustrates the effectiveness of antibiotics treatment. However, recent studies have isolated and identified bioactive compounds capable of inhibiting the growth of MRSA from endophytic microbes. Oxysporone and xylitol, purified from Heritiera fomes endophytic fungus, Pestalotia sp. have shown remarkable inhibitory activity against six strains of MRSA [97]. Likewise, El-Gendy et al. [98] have reported the efficacy of two metabolites from endophytic Streptomyces strains in the inhibition of a wide range of methicillin-resistant S. aureus.

Sources of novel lipase inhibitors (LIs)
Obesity is a considerable public health concern globally, probably, due to its association with several comorbidities, which vividly upsurge 'morbidity and mortality' risk in people with obesity [99]. Also, the incidence of obesity is on the increase in various developed nations. In fact, several obese people are living with frustration as all efforts to reduce their body mass index (BMI) through physical exercises have consistently proved abortive. Consequently, they are desperately in search of effective medications and weight loss strategy. It is intriguing that LIs may be a good alternative for such people as LIs are promising drug candidates for obesity and overweight therapy. LIs function by reducing the absorption of dietary fats in the intestine. This occurs when LIs competitively bind to lipase to prevent the breakdown of triglycerides into monoglycerides and fatty acids. Hence, LIs are capable of causing significant weight loss in obese patients [100] and as such, reducing the risk of complications such as type-2-diabetes and cardiovascular diseases. It is, therefore, important for researchers to continue to search for natural compounds with significant ability to inhibit lipase.
Interestingly, endophytes have recently been reported as promising sources of novel LIs. A ginger endophytic actinobacterial strain produced secondary metabolites with promising pancreatic lipase inhibitory activity as the percentage inhibition (≈ 90%) was significantly higher than ginger extract (≈ 69%) and standard LI (orlistat), which had approximate inhibition rate of 88% [101]. The significant lipase inhibitory activity displayed by the endophytic bacterial strain may be linked to the presence of 'terpenoids, phenols, tannins, flavonoids, alkaloids, and saponins' in the endophyte [101]. Similarly, cytosporone B and dothiorelone A, isolated from an endophytic fungus, Phomopsis sp. exhibited impressive lipase inhibitory activity as the bioactive compounds had higher IC 50 values than orlistat, used as the standard LI [102].

Drug development for coronavirus disease 2019 (COVID-19)
COVID-19, caused by 'severe acute respiratory syndrome coronavirus (SARS-CoV-2)', is a global public health concern with disturbing impacts on human race. As of 5:15 pm CET, February 15, 2021, there have been over one hundred and eight million confirmed cases of COVID-19 with about two million, three hundred and eightyone thousand, two hundred and ninety-five deaths reported worldwide [103]. At the moment, however, there exists no World Health Organization (WHO)-approved drug for the treatment of the disease. Hence, all hands must be on deck to search for potential COVID-19 medications.
Spike glycoprotein and 3CL protease are crucial in the pathogenesis and virulence of SARS-CoV-2 [104]. Thus, inhibition of these proteins is a promising COVID-19 drug discovery strategy. There are ongoing research efforts toward finding novel compounds capable of competitively inhibiting either or both CoV-2 proteins from binding its normal substrate. Molecular docking of natural antiviral compounds found in Chinese medicinal plants against spike glycoprotein and 3CL revealed some interesting results [105], thereby suggesting medicinal plants as promising bioresources for natural anti-COVID-19 compounds. Consequently, endophytes from anti-COVID-19 medicinal plants are capable of producing bioactive compounds with promising CoV-2 proteins inhibitory activity as endophytic microbes are known for secreting secondary metabolites analogues to the host plants. Therefore, endophytes from medicinal plants with confirmed antiviral properties can be explored for isolation of novel compounds with SARS-CoV-2 spike glycoprotein and 3CL protease inhibitory activity. We, thus, suggest that researchers should harness the enormous antiviral potential of endophytic microbes for the discovery of novel anti-COVID-19 drug candidates.

Promising bioresources for the development of NTDs therapeutics
NTDs are a wide range of communicable diseases with prevalence in the tropics and subtropics environments in over 140 countries [106]. There are about 18 diseases categorized by the WHO as NTDs, which include among others trachoma, buruli ulcer, leprosy, Chagas disease, leishmaniases, human African trypanosomiasis and schistosomiasis. According to WHO, NTDs affect over one billion individuals with a huge cost implication on the developing countries annually. In an attempt to prevent, control, eliminate and eradicate NTDs, the WHO developed a roadmap which suggested preventive chemotherapy and the need to strengthen the management of NTDs as some of the major strategies [107]. It is, therefore, noteworthy that bioactive compounds from endophytes have exhibited significant anti-leishmanial, antitrypanosomal and schistosomicidal activity [108][109][110][111], which suggests that secondary metabolites from endophytes are prospective candidates for the management of NTDs. However, endophytes are currently underexplored for production of potential drug candidates in the management of NTDs. As such, future research efforts should be geared toward this direction as endophytes are promising bioresources for novel natural bioactive compounds for NTDs therapeutics.

Conclusion
Endophytes have unarguably, shown great potentials for production of novel natural bioactive compounds of health significance. More so, endophytic microbes have recently emerged as natural sources of anti-MRSA compounds and LIs. Nevertheless, the promising antiviral potential of endophytes should be properly harnessed for the discovery of novel anti-COVID-19 drug candidates meanwhile, endophytes are waiting to be explored for the development of NTDs therapeutics. Given the diversity of endophytes and the characteristic biotechnological potentials in therapeutics development, endophytes are capable of contributing significantly toward ensuring good health and well-being, which are major elements of the UN SDGs.

Disclosure statement
Authors declare that they have no conflict of interest.