cutting ants to protect their fungus garden against
the pathogenic fungus Escovopsis. Proc Natl Acad
Sci USA 106:4742–4746. https://doi.org/10.1073/
pnas.0812082106
Harvey AL, Edrada-Ebel R, Quinn RJ (2015) The
re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov
14:111–129. https://doi.org/10.1038/nrd4510
Harvey CJB, Tang M, Schlecht U et al (2018) HEx: a
heterologous expression platform for the discovery of fungal natural products. Sci Adv 4:eaar5459.
https://doi.org/10.1126/sciadv.aar5459
Hautbergue T, Jamin EL, Debrauwer L et al (2018)
From genomics to metabolomics, moving toward
an integrated strategy for the discovery of fungal
secondary metabolites. Nat Prod Rep 35:147–173.
https://doi.org/10.1039/C7NP00032D
Hawksworth DL, Lu ¨cking R (2017) Fungal diversity
revisited: 2.2 to 3.8 million species. In: The fungal
kingdom. American Society of Microbiology,
Washington, DC, pp 79–95
Heine D, Holmes NA, Worsley SF et al (2018) Chemical
warfare between leafcutter ant symbionts and a coevolved pathogen. Nat Commun 9:2208. https://
doi.org/10.1038/s41467-018-04520-1
Heneghan MN, Yakasai AA, Halo LM et al (2010)
First heterologous reconstruction of a complete
functional fungal biosynthetic multigene cluster.
ChemBioChem 11:1508–1512. https://doi.org/
10.1002/cbic.201000259
Hertweck C (2015) Decoding and reprogramming complex polyketide assembly lines: prospects for synthetic biology. Trends Biochem Sci 40:189–199.
https://doi.org/10.1016/j.tibs.2015.02.001
Hoefgen S, Lin J, Fricke J et al (2018) Facile assembly
and fluorescence-based screening method for
heterologous expression of biosynthetic pathways
in fungi. Metab Eng 48:44–51. https://doi.org/
10.1016/j.ymben.2018.05.014
Hong EJ, Kim NK, Lee D et al (2015) Overexpression of
the laeA gene leads to increased production of
cyclopiazonic acid in Aspergillus fumisynnematus.
Fungal Biol 119:973–983. https://doi.org/10.1016/j.
funbio.2015.06.006
Horai H, Arita M, Kanaya S et al (2010) MassBank: a
public repository for sharing mass spectral data
for life sciences. J Mass Spectrom 45:703–714.
https://doi.org/10.1002/jms.1777
Hover BM, Kim SH, Katz M et al (2018) Cultureindependent discovery of the malacidins as
calcium-dependent antibiotics with activity against
multidrug-resistant Gram-positive pathogens.
Nat Microbiol 3:415–422. https://doi.org/10.1038/
s41564-018-0110-1
Iqbal HA, Low-Beinart L, Obiajulu JU, Brady SF (2016)
Natural product discovery through improved
functional metagenomics in Streptomyces. J Am
Chem Soc 138:9341–9344. https://doi.org/10.1021/
jacs.6b02921
Janevska S, Arndt B, Baumann L et al (2017) Establishment of the inducible Tet-On system for the activation of the silent trichosetin gene cluster in
Fusarium fujikuroi. Toxins (Basel) 9:126. https://
doi.org/10.3390/toxins9040126
Jinek M, Chylinski K, Fonfara I et al (2012) A programmable dual-RNA-guided DNA endonuclease in
adaptive bacterial immunity. Science 337:816–
821. https://doi.org/10.1126/science.1225829
Kakule TB, Zhenjian L, Schmidt EW (2014) Combinatorialization of fungal polyketide synthaseÀpeptide
synthetase hybrid proteins. J Am Chem Soc
136:17882–17890. https://doi.org/10.1021/ja511087p
Kakule TB, Jadulco RC, Koch M et al (2015) Native
promoter strategy for high-yielding synthesis and
engineering of fungal secondary metabolites. ACS
Synth Biol 4:625–633. https://doi.org/10.1021/
sb500296p
Kang HS (2017) Phylogeny-guided (meta)genome
mining approach for the targeted discovery of
new microbial natural products. J Ind Microbiol
Biotechnol 44:285–293. https://doi.org/10.1007/
s10295-016-1874-z
Kato N, Brooks W, Calvo AM (2003) The expression of
sterigmatocystin and penicillin genes in Aspergillus
nidulans is controlled by veA, a gene required for
sexual development. Eukaryot Cell 2:1178–1186.
https://doi.org/10.1128/EC.2.6.1178-1186.2003
Keilhofer N, Nachtigall J, Kulik A et al (2018) Streptomyces AcH 505 triggers production of a salicylic
acid analogue in the fungal pathogen Heterobasidion abietinum that enhances infection of Norway
spruce seedlings. Antonie Van Leeuwenhoek
111:691–704. https://doi.org/10.1007/s10482-0181017-9
Keller N, Bok J, Chung D et al (2006) LaeA, a global
regulator of Aspergillus toxins. Med Mycol 44:83–
85. https://doi.org/10.1080/13693780600835773
Khaldi N, Seifuddin FT, Turner G et al (2010) SMURF:
genomic mapping of fungal secondary metabolite
clusters. Fungal Genet Biol 47:736–741. https://doi.
org/10.1016/j.fgb.2010.06.003
Klitgaard A, Nielsen JB, Frandsen RJN et al (2015)
Combining stable isotope labeling and molecular
networking for biosynthetic pathway characterization. Anal Chem 87:6520–6526. https://doi.org/
10.1021/acs.analchem.5b01934
Kluge J, Terfehr D, Ku ¨ck U (2018) Inducible promoters
and functional genomic approaches for the genetic
engineering of filamentous fungi. Appl Microbiol
Biotechnol
102:6357–6372.
https://doi.org/
10.1007/s00253-018-9115-1
Kong FD, Huang XL, Ma QY et al (2018) Helvolic acid
derivatives with antibacterial activities against
Streptococcus agalactiae from the marine-derived
fungus Aspergillus fumigatus HNMF0047. J Nat
Prod 81:1869–1876. https://doi.org/10.1021/acs.
jnatprod.8b00382
290
M. Flak et al.
the pathogenic fungus Escovopsis. Proc Natl Acad
Sci USA 106:4742–4746. https://doi.org/10.1073/
pnas.0812082106
Harvey AL, Edrada-Ebel R, Quinn RJ (2015) The
re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov
14:111–129. https://doi.org/10.1038/nrd4510
Harvey CJB, Tang M, Schlecht U et al (2018) HEx: a
heterologous expression platform for the discovery of fungal natural products. Sci Adv 4:eaar5459.
https://doi.org/10.1126/sciadv.aar5459
Hautbergue T, Jamin EL, Debrauwer L et al (2018)
From genomics to metabolomics, moving toward
an integrated strategy for the discovery of fungal
secondary metabolites. Nat Prod Rep 35:147–173.
https://doi.org/10.1039/C7NP00032D
Hawksworth DL, Lu ¨cking R (2017) Fungal diversity
revisited: 2.2 to 3.8 million species. In: The fungal
kingdom. American Society of Microbiology,
Washington, DC, pp 79–95
Heine D, Holmes NA, Worsley SF et al (2018) Chemical
warfare between leafcutter ant symbionts and a coevolved pathogen. Nat Commun 9:2208. https://
doi.org/10.1038/s41467-018-04520-1
Heneghan MN, Yakasai AA, Halo LM et al (2010)
First heterologous reconstruction of a complete
functional fungal biosynthetic multigene cluster.
ChemBioChem 11:1508–1512. https://doi.org/
10.1002/cbic.201000259
Hertweck C (2015) Decoding and reprogramming complex polyketide assembly lines: prospects for synthetic biology. Trends Biochem Sci 40:189–199.
https://doi.org/10.1016/j.tibs.2015.02.001
Hoefgen S, Lin J, Fricke J et al (2018) Facile assembly
and fluorescence-based screening method for
heterologous expression of biosynthetic pathways
in fungi. Metab Eng 48:44–51. https://doi.org/
10.1016/j.ymben.2018.05.014
Hong EJ, Kim NK, Lee D et al (2015) Overexpression of
the laeA gene leads to increased production of
cyclopiazonic acid in Aspergillus fumisynnematus.
Fungal Biol 119:973–983. https://doi.org/10.1016/j.
funbio.2015.06.006
Horai H, Arita M, Kanaya S et al (2010) MassBank: a
public repository for sharing mass spectral data
for life sciences. J Mass Spectrom 45:703–714.
https://doi.org/10.1002/jms.1777
Hover BM, Kim SH, Katz M et al (2018) Cultureindependent discovery of the malacidins as
calcium-dependent antibiotics with activity against
multidrug-resistant Gram-positive pathogens.
Nat Microbiol 3:415–422. https://doi.org/10.1038/
s41564-018-0110-1
Iqbal HA, Low-Beinart L, Obiajulu JU, Brady SF (2016)
Natural product discovery through improved
functional metagenomics in Streptomyces. J Am
Chem Soc 138:9341–9344. https://doi.org/10.1021/
jacs.6b02921
Janevska S, Arndt B, Baumann L et al (2017) Establishment of the inducible Tet-On system for the activation of the silent trichosetin gene cluster in
Fusarium fujikuroi. Toxins (Basel) 9:126. https://
doi.org/10.3390/toxins9040126
Jinek M, Chylinski K, Fonfara I et al (2012) A programmable dual-RNA-guided DNA endonuclease in
adaptive bacterial immunity. Science 337:816–
821. https://doi.org/10.1126/science.1225829
Kakule TB, Zhenjian L, Schmidt EW (2014) Combinatorialization of fungal polyketide synthaseÀpeptide
synthetase hybrid proteins. J Am Chem Soc
136:17882–17890. https://doi.org/10.1021/ja511087p
Kakule TB, Jadulco RC, Koch M et al (2015) Native
promoter strategy for high-yielding synthesis and
engineering of fungal secondary metabolites. ACS
Synth Biol 4:625–633. https://doi.org/10.1021/
sb500296p
Kang HS (2017) Phylogeny-guided (meta)genome
mining approach for the targeted discovery of
new microbial natural products. J Ind Microbiol
Biotechnol 44:285–293. https://doi.org/10.1007/
s10295-016-1874-z
Kato N, Brooks W, Calvo AM (2003) The expression of
sterigmatocystin and penicillin genes in Aspergillus
nidulans is controlled by veA, a gene required for
sexual development. Eukaryot Cell 2:1178–1186.
https://doi.org/10.1128/EC.2.6.1178-1186.2003
Keilhofer N, Nachtigall J, Kulik A et al (2018) Streptomyces AcH 505 triggers production of a salicylic
acid analogue in the fungal pathogen Heterobasidion abietinum that enhances infection of Norway
spruce seedlings. Antonie Van Leeuwenhoek
111:691–704. https://doi.org/10.1007/s10482-0181017-9
Keller N, Bok J, Chung D et al (2006) LaeA, a global
regulator of Aspergillus toxins. Med Mycol 44:83–
85. https://doi.org/10.1080/13693780600835773
Khaldi N, Seifuddin FT, Turner G et al (2010) SMURF:
genomic mapping of fungal secondary metabolite
clusters. Fungal Genet Biol 47:736–741. https://doi.
org/10.1016/j.fgb.2010.06.003
Klitgaard A, Nielsen JB, Frandsen RJN et al (2015)
Combining stable isotope labeling and molecular
networking for biosynthetic pathway characterization. Anal Chem 87:6520–6526. https://doi.org/
10.1021/acs.analchem.5b01934
Kluge J, Terfehr D, Ku ¨ck U (2018) Inducible promoters
and functional genomic approaches for the genetic
engineering of filamentous fungi. Appl Microbiol
Biotechnol
102:6357–6372.
https://doi.org/
10.1007/s00253-018-9115-1
Kong FD, Huang XL, Ma QY et al (2018) Helvolic acid
derivatives with antibacterial activities against
Streptococcus agalactiae from the marine-derived
fungus Aspergillus fumigatus HNMF0047. J Nat
Prod 81:1869–1876. https://doi.org/10.1021/acs.
jnatprod.8b00382
290
M. Flak et al.