2. Natural Products from Fungi in Association
with Arthropods
Leaf cutter ants in association with mutualistic
bacteria and their forage fungi are well studied
and remarkably stable communities. For 50–60
million years, these communities have developed to a commensal relationship with the
ultimate goal of defense of the community
against attacking pathogens. In this multipartner system, the basidiomycete Leucoagaricus
gongylophorus serves as a food source to the
attine ants Acromyrmex octospinosus. The ants
culture the food fungus by feeding it gathered
plant material, as well as by grooming and
weeding the fungal garden (Currie 2001; Haeder
et al. 2009). Pathogenic fungi of the genus
Escovopsis disturb the delicate symbiosis by
overgrowing the food fungus, leading to a colony collapse. Ant colony-associated Streptomyces sp. Ao10, in turn, produces candicidin,
which can inhibit the pathogenic fungus, while
showing no effect on L. gongylophorus (Haeder
et al. 2009). There is evidence that the pathogenic fungus also features a distinct natural
product arsenal, suggested to serve as virulence
factors to promote the infection of the ant colony. Escovopsis weberi has been found to produce
cycloarthropsone
and
emodin,
polyketides that inhibit the growth of L. gongylophorus and, in the case of emodin, also the
associated streptomycete symbionts.
Furthermore, the pathogen also produced a novel
shearinine derivative, shearinine L, which shows repellent activity towards the ant (Dhodary et al. 2018).
MALDI-MS imaging revealed that in interaction assays
of the ant-associated bacteria Streptomyces CBR38 and
Streptomyces CBR59 with Escovopsis TZ49, similar
compounds are involved. Escovopsis TZ49 produced
the shearinines D, F, and J, while the bacteria produced
a number of natural products, including antifungal
compounds (Boya et al. 2017).
This network was further expanded by the
identification of two more natural products
playing a role in the interaction of leaf cutter
ants, bacteria and fungi. E. weberi produced
melinacidin IV, which inhibits ant-mutualistic
Pseudonocardia bacteria (Heine et al. 2018). In
addition, it produces shearinine D, which not
only inhibits mutualistic bacteria but also accumulates in ant workers and alters their behavior, causing them to fail to remove infected
material from the ant colony. This portrays a
complex, multilayered system of natural warfare between closely associated fungi, bacteria,
and higher eukaryotes, in which secondary
metabolites play a leading strategic role.
IV. Natural Product Discovery in
Fungi in the Age of Omics
To combat the shortcomings associated with
the classical approaches toward discovery of
novel microbe-derived bioactive compounds
based on targeted purification, the postgenomic
era offers its own set of valuable tools. The use
of omics-based techniques aimed at secondary
metabolism in fungi provides a route toward
identification of the involved genetic elements,
direct detection of natural products, as well as
insights into their role and regulation in native
environments.
A vast spectrum of omics strategies has
been developed to advance the endeavors of
secondary metabolism research: genomebased methods and bioinformatic algorithms
to identify the metabolic potential, highthroughput metabolome studies used to complement and verify the in silico predictions,
along with transcriptomic and proteomic tools
that form a link between the genomes and the
nascent metabolomes (Fig. 11.1b). As reviewed
in the following passage, the application and
integration of these strategies in fungal research
have proved fruitful in discovery of natural
products.
A. Genomics
Computational methods are routinely used to
identify biosynthetic gene clusters in the wealth
of genomic data made available in public repositories thanks to the advancements in highthroughput sequencing. Systematic analysis of
sequencing data has consistently revealed that
most fungal genomes contain more BGCs than
11 New Avenues Toward Drug Discovery in Fungi
281
with Arthropods
Leaf cutter ants in association with mutualistic
bacteria and their forage fungi are well studied
and remarkably stable communities. For 50–60
million years, these communities have developed to a commensal relationship with the
ultimate goal of defense of the community
against attacking pathogens. In this multipartner system, the basidiomycete Leucoagaricus
gongylophorus serves as a food source to the
attine ants Acromyrmex octospinosus. The ants
culture the food fungus by feeding it gathered
plant material, as well as by grooming and
weeding the fungal garden (Currie 2001; Haeder
et al. 2009). Pathogenic fungi of the genus
Escovopsis disturb the delicate symbiosis by
overgrowing the food fungus, leading to a colony collapse. Ant colony-associated Streptomyces sp. Ao10, in turn, produces candicidin,
which can inhibit the pathogenic fungus, while
showing no effect on L. gongylophorus (Haeder
et al. 2009). There is evidence that the pathogenic fungus also features a distinct natural
product arsenal, suggested to serve as virulence
factors to promote the infection of the ant colony. Escovopsis weberi has been found to produce
cycloarthropsone
and
emodin,
polyketides that inhibit the growth of L. gongylophorus and, in the case of emodin, also the
associated streptomycete symbionts.
Furthermore, the pathogen also produced a novel
shearinine derivative, shearinine L, which shows repellent activity towards the ant (Dhodary et al. 2018).
MALDI-MS imaging revealed that in interaction assays
of the ant-associated bacteria Streptomyces CBR38 and
Streptomyces CBR59 with Escovopsis TZ49, similar
compounds are involved. Escovopsis TZ49 produced
the shearinines D, F, and J, while the bacteria produced
a number of natural products, including antifungal
compounds (Boya et al. 2017).
This network was further expanded by the
identification of two more natural products
playing a role in the interaction of leaf cutter
ants, bacteria and fungi. E. weberi produced
melinacidin IV, which inhibits ant-mutualistic
Pseudonocardia bacteria (Heine et al. 2018). In
addition, it produces shearinine D, which not
only inhibits mutualistic bacteria but also accumulates in ant workers and alters their behavior, causing them to fail to remove infected
material from the ant colony. This portrays a
complex, multilayered system of natural warfare between closely associated fungi, bacteria,
and higher eukaryotes, in which secondary
metabolites play a leading strategic role.
IV. Natural Product Discovery in
Fungi in the Age of Omics
To combat the shortcomings associated with
the classical approaches toward discovery of
novel microbe-derived bioactive compounds
based on targeted purification, the postgenomic
era offers its own set of valuable tools. The use
of omics-based techniques aimed at secondary
metabolism in fungi provides a route toward
identification of the involved genetic elements,
direct detection of natural products, as well as
insights into their role and regulation in native
environments.
A vast spectrum of omics strategies has
been developed to advance the endeavors of
secondary metabolism research: genomebased methods and bioinformatic algorithms
to identify the metabolic potential, highthroughput metabolome studies used to complement and verify the in silico predictions,
along with transcriptomic and proteomic tools
that form a link between the genomes and the
nascent metabolomes (Fig. 11.1b). As reviewed
in the following passage, the application and
integration of these strategies in fungal research
have proved fruitful in discovery of natural
products.
A. Genomics
Computational methods are routinely used to
identify biosynthetic gene clusters in the wealth
of genomic data made available in public repositories thanks to the advancements in highthroughput sequencing. Systematic analysis of
sequencing data has consistently revealed that
most fungal genomes contain more BGCs than
11 New Avenues Toward Drug Discovery in Fungi
281