Bioactive natural products from endophytic fungi, isolated from higher plants, are attracting considerable attention from natural product chemists and biologists alike as indicated by the steady increase of publications devoted to this topic during recent years (113 research articles on secondary metabolites from endophytic fungi in the period of 2008–2009, 69 in 2006–2007, 36 in 2004–2005, 14 in 2002–2003, and 18 in 2000–2001). This overview will highlight the chemical potential of endophytic fungi with focus on the detection of pharmaceutically valuable plant constituents, e.g. paclitaxel, camptothecin and podophyllotoxin, as products of fungal biosynthesis. In addition, it will cover new bioactive metabolites reported in recent years (2008–2009) from fungal endophytes of terrestrial and mangrove plants. The presented compounds are selected based on their antimicrobial, antiparasitic, cytotoxic as well as neuroprotective activities. Furthermore, possible factors influencing natural product production in endophytes cultivated in vitro and hence the success of bioprospecting from endophytes are likewise discussed in this review.

Fungal endophytes from higher plants: a prolific source of phytochemicals and other bioactive natural products

Evolution of secondary metabolites in legumes (Fabaceae)

Endophyte-grass symbiosis is generally considered to be a classic example of microbe-plant symbiosis in which the fitness of the microbial symbiont and its host plant is closely linked, and thus, presumed to align the interests of partners toward mutually beneficial cooperation. Accumulating evidence seems to suggest that defensive mutualism provides the best framework for understanding plant-endophyte interactions in general. We conducted a meta-analysis of 99 published studies on 36 plant (inc. both grass and tree species), 62 herbivore and 17 predator or parasitoid taxons to test the importance of defensive mutualism in multitrophic interactions. In general, statistical perusal revealed that we still know little about these seemingly well-studied biological interactions. The conceptual framework for endophyte-grass interactions has largely been based on endophyte-plant-herbivore studies of two, economically important, artificially selected and introduced agricultural grass species, tall fescue and perennial ryegrass, and two generalist invertebrate pests. Only 10 original publications provided data of higher trophic levels. Consistent with the defensive mutualism hypothesis, the meta-analysis indicates that endophytes slightly increase grass resistance to herbivores, and the defensive mutualism appears to be most commonly detected in systemic and vertically transmitted grass endophytes compared to horizontally transmitted tree endophytes. However, variation appears to increase when higher trophic levels are considered. In addition to taxonomical bias, the literature is strongly biased toward short-term laboratory and greenhouse experiments rather than field conditions. Thus, current literature is insufficient to capture the breadth of variability inherent in the wild grass-endophyte populations and communities, and the general importance of defensive mutualism remains to be solved in future studies.

Defensive mutualism between plants and endophytic fungi

A typical character of plants is the production and storage of usually complex mixtures of secondary metabolites (SM). The main function of secondary metabolites is defense against herbivores and m...

https://journals.sagepub.com/doi/pdf/10.1177/1934578X0800300801

Plant Secondary Metabolism: Diversity, Function and its Evolution:

Summary
Plants form mutualistic symbioses with a variety of microorganisms including endophytic fungi that live inside the plant and cause no overt symptoms of infection. Some endophytic fungi form defensive mutualisms based on the production of bioactive metabolites that protect the plant from herbivores in exchange for a protected niche and nutrition from the host plant. Key elements of these symbioses are vertical transmission of the fungus through seed of the host plant, a narrow host range, and production of bioactive metabolites by the fungus.
Grasses frequently form symbioses with endophytic fungi belonging to the family Clavicipitaceae. These symbioses have been studied extensively because of their significant impacts on insect and mammalian herbivores. Many of the impacts are likely due to the production of four classes of bioactive alkaloids – ergot alkaloids, lolines, indole-diterpenes and peramine – that are distributed in different combinations among endophyte taxa.
Several legumes, including locoweeds, are associated with a toxic syndrome called locoism as a result of their accumulation of swainsonine. Species in two genera were recently found to contain previously undescribed endophytic fungi (Undifilum spp., family Pleosporaceae) that are the source of that toxin. The fungi are strictly vertically transmitted and have narrow host ranges.
Some plant species in the morning glory family (Convolvulaceae) also form symbioses with endophytic fungi of the Clavicipitaceae that produce ergot alkaloids and, perhaps in at least one case, lolines. Other species in this plant family form symbioses with undescribed fungi that produce swainsonine. The swainsonine-producing endophytes associated with the Convolvulaceae are distinct from the Undifilum spp. associated with locoweeds and the Clavicipitaceous fungi associated with Convolvulaceae.
In the establishment of vertically transmitted symbioses, fungi must have entered the symbiosis with traits that were immediately useful to the plant. Bioactive metabolites are likely candidates for such pre-adapted traits which were likely useful to the free-living fungi as well. With future research, vertically transmitted fungi from diverse clades with narrow host ranges and that produce bioactive compounds are likely to be found as important mutualists in additional plants.

https://besjournals.onlinelibrary.wiley.com/doi/pdf/10.1111/1365-2435.12076

Bioactive alkaloids in vertically transmitted fungal endophytes

Locoweeds (Astragalus and Oxytropis spp. that contain the toxic alkaloid swainsonine) cause widespread poisoning of livestock on western rangelands. There are 354 species of Astragalus and 22 species of Oxytropis in the US and Canada. Recently, a fungal endophyte, Embellisia spp., was isolated from Astragalus and Oxytropis spp. and shown to produce swainsonine. We conducted a survey of the major locoweeds from areas where locoweed poisoning has occurred to verify the presence of the endophyte and to relate endophyte infection with swainsonine concentrations. Species found to contain the fungal endophyte and produce substantial amounts of swainsonine were A. wootoni, A. pubentissimus, A. mollissimus, A. lentiginosus, and O. sericea. Astragalus species generally had higher concentrations of swainsonine than Oxytropis. Swainsonine was not detected in A. alpinus, A. cibarius, A. coltonii, A. filipes, or O. campestris. The endophyte could not be cultured from A. mollissimus var. thompsonii or A. amphioxys, but was detected by polymerase chain reaction, and only 30% of these samples contained trace levels of swainsonine. Further research is necessary to determine if the endophyte is able to colonize these and other species of Astragalus and Oxytropis and determine environmental influences on its growth and synthesis of swainsonine.

Relationship between the endophyte Embellisia spp. and the toxic alkaloid swainsonine in major locoweed species (Astragalus and Oxytropis).

Legumes belonging to the Astragalus, Oxytropis, and Swainsona genera have been noted by ranchers in the Americas, Asia, and Australia to cause a neurologic disease often referred to as locoism or peastruck. The toxin in these legumes is swainsonine, an α-mannosidase and mannosidase II inhibitor. Recent research has shown that in Astragalus and Oxytropis species swainsonine is produced by a fungal endophyte belonging to the Undifilum genus. Here Swainsona canescens is shown to harbor an endophyte that is closely related to Undifilum species previously cultured from locoweeds of North America and Asia. The endophyte produces swainsonine in vitro and was detected by PCR and culturing in S. canescens. The endophyte isolated from S. canescens was characterized as an Undifilum species using morphological and phylogenetic analyses.

Production of the alkaloid swainsonine by a fungal endophyte in the host Swainsona canescens.

New species of Undifilum, from locoweeds Astragalus lentiginosus Vitman and Astragalus mollissimus Torr., are described using morphological characteristics and molecular phylogenetic analyses as Un...

/pdf/two-new-species-of-undifilum-fungal-endophytes-of-astragalus-407u51eudl.pdf

Two new species of Undifilum, fungal endophytes of Astragalus (locoweeds) in the United States.

Swainsonine-a cytotoxic fungal alkaloid and a potential cancer therapy drug-is produced by the insect pathogen and plant symbiont Metarhizium robertsii, the clover pathogen Slafractonia leguminicola, locoweed symbionts belonging to Alternaria sect. Undifilum, and a recently discovered morning glory symbiont belonging to order Chaetothyriales. Genome sequence analyses revealed that these fungi share orthologous gene clusters, designated "SWN," which included a multifunctional swnK gene comprising predicted adenylylation and acyltransferase domains with their associated thiolation domains, a β-ketoacyl synthase domain, and two reductase domains. The role of swnK was demonstrated by inactivating it in M. robertsii through homologous gene replacement to give a ∆swnK mutant that produced no detectable swainsonine, then complementing the mutant with the wild-type gene to restore swainsonine biosynthesis. Other SWN cluster genes were predicted to encode two putative hydroxylases and two reductases, as expected to complete biosynthesis of swainsonine from the predicted SwnK product. SWN gene clusters were identified in six out of seven sequenced genomes of Metarhzium species, and in all 15 sequenced genomes of Arthrodermataceae, a family of fungi that cause athlete's foot and ringworm diseases in humans and other mammals. Representative isolates of all of these species were cultured, and all Metarhizium spp. with SWN clusters, as well as all but one of the Arthrodermataceae, produced swainsonine. These results suggest a new biosynthetic hypothesis for this alkaloid, extending the known taxonomic breadth of swainsonine producers to at least four orders of Ascomycota, and suggest that swainsonine has roles in mutualistic symbioses and diseases of plants and animals.

/pdf/swainsonine-biosynthesis-genes-in-diverse-symbiotic-and-2c24d7qkwm.pdf

Swainsonine Biosynthesis Genes in Diverse Symbiotic and Pathogenic Fungi

Fungal Endophytes of Locoweeds: A Commensal Relationship?
The gold standard to ensure correct patient positioning is represented by the maximum surgical exposure and the minimal risk of damage. The aim of this study was to analyze the complications related to patient prone positioning in spinal neurosurgical care from a nursing point of view, highlighting the measures that have to be used to prevent them.

Deana L. Baucom

Papers

Relationship between the endophyte Embellisia spp. and the toxic alkaloid swainsonine in major locoweed species (Astragalus and Oxytropis).

Production of the alkaloid swainsonine by a fungal endophyte in the host Swainsona canescens.

Two new species of Undifilum, fungal endophytes of Astragalus (locoweeds) in the United States.

Swainsonine Biosynthesis Genes in Diverse Symbiotic and Pathogenic Fungi

Fungal Endophytes of Locoweeds: A Commensal Relationship?