For centuries, plants have been a valuable source of bioactive compounds and medicinal preparations including herbal (phyto) medicines or drugs, used to prevent and treat a huge and diverse range of human and animal ailments. However, just as the community of microbes (microbiome) found within and on the bodies of animals and humans is now recognised for its discrete but important contribution to health and immunity, microorganisms that live on plants, also seem to play important functions in helping to protect and enable their survival^(1).

Endophytes are microorganisms (mostly bacteria and fungi) which reside within plant tissues in leaves, roots, flowers, seeds or stems of plants for at least part of their life cycles, without causing apparent harm to the host plant. They seem to have a neutral or symbiotic and interdependent relationship with their plant hosts, with often mutual benefits. These can include improvement in the plants ability to assimilate nutrients and resist environmental stress or insect infestation, while at the same time providing a home and other support to endophytes which can rely upon the plant metabolism for their propagation and survival. Endophytes have been found in every plant studied to date, with numbers and types found in a particular plant depending upon the host species, host developmental stage, and environmental conditions.

The complexities and inter-dependencies of plant relationships to microbes, are however much more than a fascinating area of research for plant scientists. For many reasons, endophytes are continuing to gain prominence as a potential source of compounds with high therapeutic potential, and their presence (naturally or inoculated) is increasingly been reported to influence the quality and quantity of extracts derived from medicinal plants^(2,3). Probably due to their presence in a specialized niche, endophytes are capable of synthesizing diverse types of bioactive molecules (secondary metabolites), just as plants themselves do.

Secondary metabolites include compounds such as alkaloids, peptides, steroids, terpenoids and flavonoids, and help the plant cope with environmental stressors such as drought, predators or infections, and much more. It is these compounds that also often exhibit pharmacological activities of interest, to a human or animal therapeutics domain.

In fact we’ve known about and utilised microbes living in plants for drug development for a long time now, with some well known examples. The first commercialised antibiotic penicillin, was first discovered as a secondary metabolite produced by the endophytic fungus Penicillium notatum, which Fleming noticed had the ability to destroy colonies of the bacterium Staphylococcus aureus. Despite this, only a fraction of endophytic microorganisms have been isolated and investigated for their biological activities.

Endophytes as sources of antibiotics:

Other novel antibiotic types produced by fungi or bacteria living within plants or soil, have since been characterised and commercialised, with tetracyclines and aminoglycosides, being notable examples.

In a world where the emergence of resistance to antimicrobials requires the constant development of new antibiotics, the search for new antimicrobial compounds derived from endophytes, is a key area of research^{(4, 5).} These include secondary metabolites from endophytic actinobacteria⁽⁶⁾, and endophytic fungi from macroalgae⁽⁷⁾, and a large number of promising compounds have been identified⁽⁸⁾.

Mangrove species, which are common and endemic plants in coastal ecosystems, seem to be an ideal source of promising bioactive endophytic compounds⁽⁹⁾, due perhaps to their interface between the world of plants, mud, and the sea.  Compounds characterised to date have shown cytotoxic, antibacterial, antifungal, α-glucosidase inhibitory, protein tyrosine phosphatase B inhibitory, and antiviral activities. Antibacterial examples include secondary metabolites produced by the fungus Alternaria spp, an endophyte of the Chinese mangrove species Sonneratia alba, which show broad antimicrobial activity against several multidrug-resistant bacterial strains⁽¹⁰⁾.  Phomopsis species of endophytic fungi found in mangroves and various other plants, produce various antibacterial compounds⁽¹¹⁾, and flavonoid and cinnamic acid compounds made by an endophytic fungus that inhabits Cinnamomum species, show good activity against the tuberculosis bacteria(¹²⁾. Bacterial communities colonizing different plant parts of Echinacea purpurea, may also contribute to its well-known immune enhancing, and possible antibacterial activities⁽¹³⁾.

Among the many different regulators of antibiotic drug resistance, drug transporter molecules which pump or keep the antibiotic(s) out of the bacterial cell, are considered to be key contributors to the development of multidrug resistance. Research is finding, however, that various endophytes can act as novel drug resistance reversal agents, by inhibiting these drug transporters⁽¹⁴⁾.

Disruption of bacterial intercellular communication processes controlling virulence known as quorum-sensing, is also a worthwhile strategy being pursued to help reduce pathogenesis within infectious bacteria. Endophytic microbes provide a plethora of such quorum-sensing inhibitor molecules⁽¹⁵⁾.

Cytotoxics

Bioprospecting and screening of plant endophyte communities has been the source of novel anticancer drugs such as paclitaxel (taxol) first discovered in the bark of the Pacific yew tree, Taxus brevifolia, in 1970^{(16, 17)}. A major limitation on the use of taxol as a drug has been its short supply because of the yew tree’s slow growth and extremely low yield of taxol. To meet the large demand for taxol, other production methods have been researched and developed.  

These include the application of semi synthesis, biocatalysis and fermentation by fungi^{(18, 19)}. The first endophytic taxol-producing fungus, Taxomyces andreanae, was discovered in T. brevifolia in 1993 ⁽²⁰⁾, and others have subsequently been reported. Since then new techniques in biotechnology, have increased the extraction yield from taxol-producing fungi. These have the potential to increase the efficiency of taxol extraction for a more sustainable production of taxol and related drugs ⁽²¹⁾. 

In addition to being sources of taxol, endophytic fungi from terrestrial, mangrove and marine sources produce other bioactive metabolites that hold promise as potential anticancer agents^{(22, 23)}.  Endophytic fungi derived from various seaweeds, have also been found to be good sources of anticancer compounds ^(24)..

Other applications:

Health depends on the diet, which influences the gut microbiota (and vice versa), and evidence suggests some members of the herbivore gut microbiome derive directly from being common plant microbes⁽²⁵⁾. 

Endophytes produce a wide range of compounds exhibiting anti-inflammatory activities, including against nitric oxide, tumor necrosis factor, and reactive oxygen species (NO, TNF-α, and ROS)⁽²⁶⁾. Endophytic fungi also appear to be a wealthy pool of potential antimalarial agents, sorely needed due to increasing resistance to currently available antimalarial drugs and insecticides⁽²⁷⁾.

Apart from being a source of medicines, various applications of plant endophytes in agriculture are suggested. 

In New Zealand, researchers recovered 192 culturable bacteria from the leaves, stems and roots of the New Zealand native mānuka, and found some bacterial isolates to have good activity against two fungal pathogens, as well as the bacterial pathogen Pseudomonas syringae pv. Actinidiae ⁽²⁸⁾. This microbe is responsible for the notorious Psa infection in kiwifruit, suggesting yet another potential use for mānuka in New Zealand agriculture.

Propagules, the reproductive units of mangroves, have recently been found to host beneficial bacteria that enhance the potential of mangrove seedlings establishment, and confer salt tolerance to cereal crops⁽²⁹⁾. These bacteria may therefore have useful applications, in a world where sea levels are rising.

Increasing the sustainability of future agriculture will required a reduced dependency on use of disease-controlling and often cumulative chemicals such as synthetic fungicides, herbicides and organophosophates pesticides, in order to produce healthy plants and animals, while ensuring our soils remain healthy for future generations. Plants themselves, and the endophytes that they have a cohabitation relationship with, seem like good sources for more natural and less harmful disease control agents.

In the past we used pigs and horses to produce drugs such as insulin and other hormones. Future novel drug discovery as well as the ability to scale up production of known medicinal secondary metabolites found in plants or existing expensive new drugs, would seem to have a fertile spawning ground in the form of the fungi and bacteria that like to live within plants. However, as microbes like to remind us on a regular basis, in doing so, ensuring we respect their evolutionary skills and don’t adversely undermine the interconnectedness of their complex relationships with the rest of nature, will be a critical requirement.

References:

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