including those from fungi, should hold the
key to tackling the problem of missing antiinfective drugs and increasing antimicrobial
resistance.
Despite the apparent simplicity of such
claims, the issue is fundamentally complex
and multilayered. Initially, a considerable effort
is needed to subject a newly isolated compound
to relevant bioactivity testing—a task to which
many research groups are ill-equipped. Subsequently, there is a long (and financially
demanding) way to go between the detection
of a biological activity of a compound and its
potential introduction to the market as a drug.
This difficult endeavor is further hindered by
the reluctance of large pharmaceutical companies to engage and invest considerable capital
in antimicrobial products, which have a short
life span and a low, if not negative, net value
(Cooper and Shlaes 2011).
Integrative approaches inside the lab, as
well as in collaborative efforts between academic researchers, the industry, and regulatory
bodies, will be crucial in overcoming the threat
of antimicrobial resistance and the introduction of novel antibiotics into clinical practice.
With their predicted ecological diversity and
secondary metabolic capacity, fungi will
undoubtedly prove to be an influential source
of lead molecules.
References
Abdelwahab MF, Kurta ´n T, Ma ´ndi A et al (2018)
Induced secondary metabolites from the endophytic fungus Aspergillus versicolor through bacterial co-culture and OSMAC approaches.
Tetrahedron Lett 59:2647–2652. https://doi.org/
10.1016/j.tetlet.2018.05.067
Acharya D, Miller I, Cui Y et al (2019) omics technologies to understand activation of a biosynthetic
gene cluster in Micromonospora sp. WMMB235:
deciphering keyicin biosynthesis. ACS Chem Biol
14:1260–1270. https://doi.org/10.1021/acschembio.9b00223
Ahuja M, Chiang YM, Chang SL et al (2012) Illuminating the diversity of aromatic polyketide synthases
in Aspergillus nidulans. J Am Chem Soc 134:8212–
8221. https://doi.org/10.1021/ja3016395
Alberti F, Foster GD, Bailey AM (2017) Natural products from filamentous fungi and production
by heterologous expression. Appl Microbiol
Biotechnol 101:493–500. https://doi.org/10.1007/
s00253-016-8034-2
Albright JC, Goering AW, Doroghazi JR et al (2014)
Strain-specific proteogenomics accelerates the discovery of natural products via their biosynthetic
pathways. J Ind Microbiol Biotechnol 41:451–459.
https://doi.org/10.1007/s10295-013-1373-4
Amos GCA, Awakawa T, Tuttle RN et al (2017) Comparative transcriptomics as a guide to natural product
discovery and biosynthetic gene cluster functionality. Proc Natl Acad Sci U S A 114:E11121–E11130.
https://doi.org/10.1073/pnas.1714381115
Andersen MR, Nielsen JB, Klitgaard A et al (2013)
Accurate prediction of secondary metabolite
gene clusters in filamentous fungi. Proc Natl
Acad Sci U S A 110:E99–E107. https://doi.org/
10.1073/pnas.1205532110
Anyaogu DC, Mortensen UH (2015) Heterologous production of fungal secondary metabolites in Aspergilli. Front Microbiol 6:77. https://doi.org/10.3389/
fmicb.2015.00077
Arsenault P, Wobbe K, Weathers P (2008) Recent
advances in artemisinin production through heterologous expression. Curr Med Chem 15:2886–
2896. https://doi.org/10.2174/092986708786242813
Azzollini A, Boggia L, Boccard J et al (2018) Dynamics
of metabolite induction in fungal co-cultures by
metabolomics at both volatile and non-volatile
levels. Front Microbiol 9:72. https://doi.org/
10.3389/fmicb.2018.00072
Bailey AM, Alberti F, Kilaru S et al (2016) Identification
and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased
rapid antibiotic production. Sci Rep 6:25202.
https://doi.org/10.1038/srep25202
Bayram O ¨ , Braus GH (2012) Coordination of secondary
metabolism and development in fungi: the
velvet family of regulatory proteins. FEMS Microbiol Rev 36:1–24. https://doi.org/10.1111/j.15746976.2011.00285.x
Be ´rdy J (2005) Bioactive microbial metabolites. J
Antibiot (Tokyo) 58:1–26. https://doi.org/10.1038/
ja.2005.1
Bergmann S, Schu ¨mann J, Scherlach K et al (2007)
Genomics-driven discovery of PKS-NRPS hybrid
metabolites from Aspergillus nidulans. Nat Chem
Biol 3:213–217. https://doi.org/10.1038/nchembio869
Bergmann S, Funk AN, Scherlach K et al (2010) Activation of a silent fungal polyketide biosynthesis
pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster.
Appl Environ Microbiol 76:8143–8149. https://doi.
org/10.1128/AEM.00683-10
Billingsley JM, DeNicola AB, Tang Y (2016) Technology development for natural product biosynthesis
in Saccharomyces cerevisiae. Curr Opin Biotechnol
42:74–83.
https://doi.org/10.1016/j.copbio.2016.02.033
11 New Avenues Toward Drug Discovery in Fungi
287
key to tackling the problem of missing antiinfective drugs and increasing antimicrobial
resistance.
Despite the apparent simplicity of such
claims, the issue is fundamentally complex
and multilayered. Initially, a considerable effort
is needed to subject a newly isolated compound
to relevant bioactivity testing—a task to which
many research groups are ill-equipped. Subsequently, there is a long (and financially
demanding) way to go between the detection
of a biological activity of a compound and its
potential introduction to the market as a drug.
This difficult endeavor is further hindered by
the reluctance of large pharmaceutical companies to engage and invest considerable capital
in antimicrobial products, which have a short
life span and a low, if not negative, net value
(Cooper and Shlaes 2011).
Integrative approaches inside the lab, as
well as in collaborative efforts between academic researchers, the industry, and regulatory
bodies, will be crucial in overcoming the threat
of antimicrobial resistance and the introduction of novel antibiotics into clinical practice.
With their predicted ecological diversity and
secondary metabolic capacity, fungi will
undoubtedly prove to be an influential source
of lead molecules.
References
Abdelwahab MF, Kurta ´n T, Ma ´ndi A et al (2018)
Induced secondary metabolites from the endophytic fungus Aspergillus versicolor through bacterial co-culture and OSMAC approaches.
Tetrahedron Lett 59:2647–2652. https://doi.org/
10.1016/j.tetlet.2018.05.067
Acharya D, Miller I, Cui Y et al (2019) omics technologies to understand activation of a biosynthetic
gene cluster in Micromonospora sp. WMMB235:
deciphering keyicin biosynthesis. ACS Chem Biol
14:1260–1270. https://doi.org/10.1021/acschembio.9b00223
Ahuja M, Chiang YM, Chang SL et al (2012) Illuminating the diversity of aromatic polyketide synthases
in Aspergillus nidulans. J Am Chem Soc 134:8212–
8221. https://doi.org/10.1021/ja3016395
Alberti F, Foster GD, Bailey AM (2017) Natural products from filamentous fungi and production
by heterologous expression. Appl Microbiol
Biotechnol 101:493–500. https://doi.org/10.1007/
s00253-016-8034-2
Albright JC, Goering AW, Doroghazi JR et al (2014)
Strain-specific proteogenomics accelerates the discovery of natural products via their biosynthetic
pathways. J Ind Microbiol Biotechnol 41:451–459.
https://doi.org/10.1007/s10295-013-1373-4
Amos GCA, Awakawa T, Tuttle RN et al (2017) Comparative transcriptomics as a guide to natural product
discovery and biosynthetic gene cluster functionality. Proc Natl Acad Sci U S A 114:E11121–E11130.
https://doi.org/10.1073/pnas.1714381115
Andersen MR, Nielsen JB, Klitgaard A et al (2013)
Accurate prediction of secondary metabolite
gene clusters in filamentous fungi. Proc Natl
Acad Sci U S A 110:E99–E107. https://doi.org/
10.1073/pnas.1205532110
Anyaogu DC, Mortensen UH (2015) Heterologous production of fungal secondary metabolites in Aspergilli. Front Microbiol 6:77. https://doi.org/10.3389/
fmicb.2015.00077
Arsenault P, Wobbe K, Weathers P (2008) Recent
advances in artemisinin production through heterologous expression. Curr Med Chem 15:2886–
2896. https://doi.org/10.2174/092986708786242813
Azzollini A, Boggia L, Boccard J et al (2018) Dynamics
of metabolite induction in fungal co-cultures by
metabolomics at both volatile and non-volatile
levels. Front Microbiol 9:72. https://doi.org/
10.3389/fmicb.2018.00072
Bailey AM, Alberti F, Kilaru S et al (2016) Identification
and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased
rapid antibiotic production. Sci Rep 6:25202.
https://doi.org/10.1038/srep25202
Bayram O ¨ , Braus GH (2012) Coordination of secondary
metabolism and development in fungi: the
velvet family of regulatory proteins. FEMS Microbiol Rev 36:1–24. https://doi.org/10.1111/j.15746976.2011.00285.x
Be ´rdy J (2005) Bioactive microbial metabolites. J
Antibiot (Tokyo) 58:1–26. https://doi.org/10.1038/
ja.2005.1
Bergmann S, Schu ¨mann J, Scherlach K et al (2007)
Genomics-driven discovery of PKS-NRPS hybrid
metabolites from Aspergillus nidulans. Nat Chem
Biol 3:213–217. https://doi.org/10.1038/nchembio869
Bergmann S, Funk AN, Scherlach K et al (2010) Activation of a silent fungal polyketide biosynthesis
pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster.
Appl Environ Microbiol 76:8143–8149. https://doi.
org/10.1128/AEM.00683-10
Billingsley JM, DeNicola AB, Tang Y (2016) Technology development for natural product biosynthesis
in Saccharomyces cerevisiae. Curr Opin Biotechnol
42:74–83.
https://doi.org/10.1016/j.copbio.2016.02.033
11 New Avenues Toward Drug Discovery in Fungi
287