Appl Biochem Biotechnol

DOI 10.1007/s12010-015-1783-z

The Chemical Diversity of the Ascomycete Fungus

Paecilomyces variotii

Roberto Mioso 1 & Francisco Javier Toledo Marante 2 &

Irma Herrera Bravo de Laguna 3

Received: 23 December 2014 / Accepted: 27 July 2015

# Springer Science+Business Media New York 2015

Abstract Paecilomyces variotii isolated from a broad range of habitats drives the diversifica-
tion of new high-value-added secondary metabolites that could potentially play an important
role in human and animal health. These metabolites include the anhydride metabolite of the
nonadride family, as well as the following compounds: naphthopyranone metabolites,
sphingofungins, eicosenoic acids, new branched fatty acids, ascofuranone, polyketides, an
anacardic acid analogue, straight-chain peptides, and volatile compounds. These natural
products show that P. variotii can provide leading compounds for new drug discoveries, which
may include herbicide agents, some of which are important in the agrochemical market.
Finally, this review outlines recent developments, trends, and prospects for the chemistry of
this ascomycete.

Keywords Paecilomyces variotii . Byssochlamys spectabilis . Fungus . Secondary metabolites .

Bioactive compounds

Electronic supplementary material The online version of this article (doi:10.1007/s12010-015-1783-z)

contains supplementary material, which is available to authorized users.
Highlights • Paecilomyces variotii fungus efficiently produces secondary metabolites.
• Bioactive compounds produced by P. variotii are reviewed.
• Research focused on high-value products obtained from P. variotii fungus.

* Irma Herrera Bravo de Laguna

ictiocentauros@hotmail.com

1
Department of Biochemistry, Federal University of Pernambuco - UFPE, Recife, Pernambuco
50740-465, Brazil
2
Department of Chemistry, University of Las Palmas de Gran Canaria - ULPGC, 35017 Las Palmas de
Gran Canaria, Spain
3
Department of Biology, University of Las Palmas de Gran Canaria - ULPGC, 35017 Las Palmas de
Gran Canaria, Spain
 Appl Biochem Biotechnol

Introduction

Paecilomyces variotii is a thermophilic saprotroph fungus that experiences aggressive and

rapid growth and is adaptable to adverse environmental conditions. It is the asexual state of
Byssochlamys spectabilis and belongs to the Eurotiales order, Trichocomaceae family [1].
However, the Byssochlamys state is rarely observed for this culture, due to the heterothallic
nature of this species [2, 3].
P. variotii is found worldwide and commonly occurs in air, soil, and plant litter. It is
frequently recovered from aquatic environments where it probably resides as dormant conidia
or ascospores [4–8], and it is also associated with many types of human infections [9]. As a
contaminant mould, this fungus can also spoil a wide range of food and feedstuff. It is
frequently encountered in heat-treated industrial products, since it can withstand brief exposure
of temperatures at 80–100 °C for up to 15 min [2, 10, 11].
Filamentous fungi are essential organisms in nature for the degradation of plant material
and geochemical cycling of nutrients, and they are biotrophs and parasites for plants and
animals; however, a few of these organisms have adversely affected modern society, primarily
as pathogens of crops and humans. They also provide drug leads and enzymes for biotechno-
logical applications [12].
The hyperdiversity of fungi and the heterogeneity of their habitats drive the diversification
of new high-value secondary metabolites that could play an important role in human and
animal health. Therefore, this review provides concise information about the chemical diver-
sity found in the fungus P. variotii. A bibliographic search was performed of the SciFinder,
ScienceDirect, and PubMed databases, using the following keyword combinations:
BPaecilomyces and variotii^ and Bcornexistin and synthesis.^
Subsequently, 52 references closely related to the scope of the review were selected. The
following substances were described: naturally occurring anhydride compounds from the
nonadride family, naphthopyranone metabolites, sphingofungins, eicosenoic acids, new
branched fatty acids, ascofuranone, polyketides, an anacardic acid analogue, straight-chain
peptides, and volatile metabolites. The studies also showed that P. variotii and its active
principles are more likely to provide leading compounds for new drug discoveries, which
may include chemopreventive agents possessing immunomodulatory and anticancer
bioactivity.

Metabolites from Paecilomyces variotii and Their Biological Activities

Filamentous ascomycete genomes encode a broad spectrum of enzymes that synthesize

secondary metabolites, including nonribosomal peptide synthetases, polyketide synthases,
and terpene synthases [13]. Consequently, these microfungi are able to produce, store, and
release allelochemicals that affect other organisms and determine the existence of chemical
interactions which give the producer adaptive advantages [14–16].
Several of these secondary metabolites are produced on a commercial scale and are used for
treating diseases; however, some of these metabolites are toxic in nature, so efforts are being
made to reduce their production [17]. In fact, during the fermentation process, fungi produce
an enormous array of small bioactive molecules, including antibiotics, antitumor compounds,
antivirals, antiparasitic agents, immunosuppressants, and toxins, some of which are important
in the pharmaceutical and agrochemical markets [18, 19].
Appl Biochem Biotechnol

The filamentous fungus P. variotii has been extensively studied over the last decades, and it
has been shown to be an intriguing source of new bioactive natural products. Widely involved
in the fundamental degradation processes found in nature, it produces a variety of secondary
metabolites when grown on various types of substrata.

Cornexistin and Hydroxycornexistin

Cornexistin (1, Fig. 1) was originally isolated in 1987 from a culture filtrate of P. variotii
during a guided screening of new microbial products possessing herbicidal activity. This
compound was characterized by NMR spectroscopy and X-ray crystallographic studies, and
its structure and molecular formula (C16H20O6) were confirmed by Takahashi et al. [20].
A phytotoxicity bioassay was performed by Amagasa et al. and it revealed the physiolog-
ical effects of cornexistin on duckweed (Lemna paucicostata)—a pronounced inhibition of its
growth within 72 h [21]. Based on the timing of application, cornexistin can be characterized
as a post-emergence herbicide which is active against young annual and perennial, and mono-
and dicotyledonous plants. Five true grass weeds (e.g., Echinochloa crus-galli) and five broad
leaf weeds (e.g., Abutilon theopharasti) were tested by Takeshiba et al. [22]. Selective
protection was observed for corn because cornexistin has the added benefit of being essentially
inactive towards edible Gramineae plants [23, 24].
Cornexistin and its oxidized derivative, hydroxycornexistin (2), are members of the nonadride
family of natural products. Cornexistin is sensitive to decomposition in the presence of acid,
base, and light. Used alone or in conjunction with traditional chemicals, this biorational herbicide
can improve crop quality and productivity, and it has a low impact on the environment [25].
As a result of these agrochemical applications, a range of efforts have been dedicated to
obtaining these alleloherbicides [26]. Takeshiba et al. biosynthesized some new derivatives
from cornexistin (3, R1, R2 = CO2H, CONH2; R1, R2 = C(:X)YC(:Z), X, Y, Z = O, NH; R3,
R6 = OH, SH, NH2, X; R4, R5 = H, OH; or R4, R5 = O, NH; A = simple bond, O; and the SH,
NH2, CO2H, CONH2, and NH groups) [22]. The OH, SH, and NH2 groups can be protected or
transformed in the form of their salts. They were tested as inhibitors of germination, herbicides,
and growth regulators of plants (phytohormones).

Fig. 1 Cornexistin (1), hydroxycornexistin (2), and derivatives (3)

 Appl Biochem Biotechnol

Similarly, Fields et al. prepared hydroxycornexistin (2) through the fermentation of

P. variotii [27]. This phytochemical and its free dibasic acid, diester, monoester, monoamide,
monothio esters, and salts are selective herbicides for broad-spectrum broadleaf and grass
weed control in corn cultivation.
Cornexistin is too complex to be synthesized economically. Recently, the genetics behind
the biosynthesis of cornexistin have been investigated in order to manipulate the pathway. The
genome of P. variotii has been sequenced and analyzed for potential gene clusters related to the
biosynthetic pathway of nonadride cornexistin [28]. A number of techniques, such as hetero-
logous expression and overexpression of pathway regulators, are being utilized to improve titer
and biosynthesized precursors and analogues for structure activity relationship testing of these
filamentous fungi [29]. This approach assumes a new option for the production of these
molecules and it is an excellent alternative to the synthetic chemical proposal.

A Cyclic Anhydride

Aldridge et al. reported the isolation and reactions of an anhydride (4) from P. variotii. The
structure of compound 4 was determined by standard chemical and physical methods [30]. It
underwent methylation to give the ester (5), and its reaction with PhNH2 and with NH3 gives
the compounds 6 and 7, respectively (Fig. 2).

Polyphenols

Ayer et al. isolated a strain of P. variotii from pine beetle larvae, which was cultivated in a
liquid medium, and two new metabolites were extracted with the 1H-nafto[2,3-c] piran-1-one
skeleton [31]. Their molecular structures—semiviriditoxin (8) and semiviriditoxic acid (9)—
were elucidated by chemical and spectroscopic methods. Later, the first total synthesis and the
absolute stereochemistry of semiviriditoxin were confirmed as a naphthopyranone metabolite
from the said fungus [32] (Fig. 3).
Jung et al. suggested that the extract of P. variotii is effective for preventing and treating
infections caused by fish pathogenic microorganisms, particularly Streptococcus iniae,
Aeromonas hydrophila, A. sobria, Edwardsiella tarda, Vibrio parahaemolyticus, V. cholerae,
V. vulnificus, V. ichthyoenteri, Clostridium botulinum, and Mycobacterium marinum [33]. The
effectiveness of these extracts has been attributed to viriditoxin (10), a known compound
isolated previously from Aspergillus viridinutans, which has been shown to be toxic against
several pathogenic bacteria [34]. Therefore, the use of this naturally occurring antibiotic in
aquaculture could improve the safeness of fish consumption, since it generates a lower
environmental impact because of its low toxicity and rapid degradation [35].

Fig. 2 Anhydride (4) and the derivatives (5, 6, and 7) from P. variotii
Appl Biochem Biotechnol

Fig. 3 Semiviriditoxin (8), semiviriditoxic acid (9), and viriditoxin (10)

Sphingolipids

Other new antifungals have been isolated from P. variotii. Sphingofungins E and F (11 and 12,
Fig. 4), for example, were recovered from the whole fermentation broth of P. variotii [36]. Like
sphingofungin B, both compounds inhibited serine palmitoyltransferase at nanomolar levels.
Furthermore, sphingofungin E showed fungicidal activity against several human pathogens
[37].

Eicosenoic Acids and Polysaccharides

Horn et al. reported two eicosenoic acids with fungicidal activity in the culture broth of
P. variotii [38], while Leal studied the structure of water-soluble polysaccharides from this
fungus, via GC, GC-MS, and NMR analysis [39]. These studies were also extended to the cell
wall polysaccharides of four strains of the same fungus [40].

Fig. 4 Sphingofungins E (11) and F (12)

 Appl Biochem Biotechnol

A Branched Fatty Acid and Pigments

Finally, the lipid composition and its hydrosoluble polysaccharide structure were determined
through GC, GC-MS, and NMR spectroscopy, resulting in the identification of a new
carboxilic acid—neo-iso-pentadecanoic acid [41, 42]. And more recently, Babitskaya and
Shcherba provided new insights into the nature of melanin, its pigment [43].

A Prenylated Phenol

A compound of cytotoxic substances was isolated from the fermented culture broth of
P. variotii. The main component of this mixture was identified as ascofuranone (13, Fig. 5),
which is an antibiotic that had been discovered in Ascochyta viciae [44]. Strain INA-199, a
new producer of ascofuranone, was assigned to this isolated P. variotii [45].

Polyketides

Four new antibacterial polyketides (14–17, Fig. 6) were characterized from a P. variotii strain
isolated from the giant jellyfish Nemopilema nomurai. The compounds inhibited growth of
pathogenic bacteria, including methicillin-resistant Staphylococcus aureus 3089 and
multidrug-resistant V. parahemolyticus, with MIC values in the range of 5–40 μg mL−1 [46].

An Anacardic Acid Analogue

In the continuing search for additional bioactive metabolites, a naturally occurring anacardic
acid analogue (18, Fig. 7) was isolated from the aforementioned jellyfish-derived fungal strain.
The new compound showed cytotoxicity against human and marine pathogens, including
multidrug-resistant strains. Liu et al. reported that this natural analogue also exhibits mild
antibacterial activity against Escherichia coli DC2, Streptococcus iniae FP5228, and
methicillin-resistant S. aureus (MRSA) [47].

Peptides

Two novel antifungals—SCH 643432 and an isomer—were isolated from the P. variotii
fermentation broth. The compounds were identified as straight-chain peptides containing
several amino acids, including alanine, aminoisobutyric acid, proline, leucine, glycine, and
arginine. The N-terminal ends in a previously identified ß-keto acid: 2-Me 3-oxo tetradecanoic

Fig. 5 Ascofuranone (13)

Appl Biochem Biotechnol

Fig. 6 New polyketides (14–17)

acid. Both compounds were active against invasive fungi like Aspergillus and Candida
species, as well as various dermatophytes [48].

Volatile and Nonvolatile Compounds

Fungi are able to interact with their environment by emitting volatile organic compounds like
allelochemicals. Due to this, P. variotii was cultivated on two different media and its volatile
metabolites were extracted by head-space solid phase micro-extraction and then analyzed by
GC-MS. The results indicate that various hydrocarbons, alcohols, ketones, ethers, esters,
sulfur-containing compounds, and terpenes were identified. The most commonly produced
substances were as follows: 2-methyl-1-propanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 3-

Fig. 7 Chemical structure of the anacardic acid analogue (18) isolated from a cnidarian-derived strain of
P. variotii
 Appl Biochem Biotechnol

Fig. 8 Chemical structure of ergosterol peroxide (19) isolated from a marine-derived strain of P. variotii

methylfuran, and dimethyl disulfide. It was concluded that the production of volatile com-
pounds is highly dependent on the culture media [41].
More recently, a new strain of P. variotii was isolated from a marine habitat. A total of 28
structural groups of volatile organic compounds were identified by GC-MS from liquid-
fermented biomass, and they were mainly normal lipid compounds involved in the fatty acid
pathway, fragments from the catabolism of P. variotii, terpenoids, and a metabolite from the
shikimic acid route. Additionally, two nonvolatile constituents — triolein and ergosterol
peroxide (19, Fig. 8) — were isolated and identified by spectroscopy [8, 49]. The metabolic
profile found in the mycelium of the new isolate suggests its potential use as a natural source to
produce high-value molecules with nutritional and functional properties.
At a concentration of 25 μM, ergosterol peroxide (19) completely inhibits growth and
induces apoptosis of HL-60 cells [50]. It also suppresses inflammatory responses in RAW264.7
macrophages and the growth of HT29 colon adenocarcinoma cells [51], and it has inhibitory
effects on human MCF-7 breast adenocarcinoma cells by inducing cell apoptosis [52].

Conclusions and Perspectives

Current drug discovery research of filamentous fungi involves a multifaceted approach

combining mycological, biochemical, pharmacological, metabolic, biosynthetic, and molecu-
lar techniques. However, despite the increasing discovery of new metabolites for these
microorganisms, there is still a huge gap in the knowledge of the biosynthetic pathways for
the sustainable production of bioactive compounds.
This review has shown that the ascomycete fungus P. variotii has a limited degree of
structural diversity and most of the established structures are secondary metabolites that are
probably derived from fatty acids, aminoacids, polysaccharides, polyketides, and the isopren-
oid biosynthetic pathway (see the summary in Table S1 in the electronic supplementary
material). Although the compounds have relatively simple structures, they have inspired
interest in the synthetic chemistry, pharmaceutical, agrochemical, and fine chemical industries
because of their interesting biological and pharmacological properties. It is expected that this
review will create new research opportunities for improving investigation of the chemistry of
this fungus which has immense potential for various biotechnological applications.

Conflict of Interest The authors declare that they have no competing interests.
Appl Biochem Biotechnol

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