Secondary Metabolites and Their Bioactivities Produced by Paecilomyces

Paecilomyces, a common saprobic filamentous fungus, not only plays an important role in biological control, but also has applications in medicine, food, and environmental protection. In this paper, 223 secondary metabolites and their bioactivities from 13 known species and various unidentified strains of Paecilomyces are reviewed. Their structures can be described as polyketide, terpenoid, peptide, alkaloid, quinone, pyrone, sterol, and fatty acid. They have been demonstrated varying biological activities, including antimicrobial, antitumor, insecticidal, antiplasmodial, antimalarial, nematicidal, herbicidal, and enzyme-inhibiting. This review provides a comprehensive overview of secondary metabolites and their biological activities from strains of Paecilomyces.


Introduction
Paecilomyces is a common saprobic filamentous fungus. It is found in a wide range of habitats, including soils, forests, grassland, deserts, sediments, and even sewage sludge [1]. Paecilomyces belongs to the phylum Ascomycota, and the order Eurotiales, which has septate, branching hyphae, bearing long chains of conidia from the tips of conidiophores, and flask-to oval-shaped or subglobose phialide. Colonies of Paecilomyces are at first floccose and white, then become different colors. Paecilomyces strains do not harm to health in general and are in occasion opportunistic in humans and mammals.
Many species of Paecilomyces are important entomopathogenic fungi, which refer to a class that can infect or parasitize living host organisms and are an ecologically highly specialized group of micro-organisms. Entomopathogenic fungi are well known for their ability to produce various bioactive compounds during infection and proliferation in insects, and are considered as potential sources of novel bioactive compounds. The entomopathogenic fungi belonging to the genus Paecilomyces have been extensively studied as potential biological control agents against insects. Besides, Paecilomyces species have been used as Chinese traditional medicine to treat impotence, sedation, analgesia, backache, cancer, memory loss, and also as a tonic to nourish the lungs and kidneys [2]. Moreover, strains of Paecilimyces can survive in a wide range of temperatures and pH, which allows them to grow in a variety of substrates and makes them a rich source of biologically active natural products [3].
A peptidic antibiotic, leucinostatin D (7), was obtained from P. marquandii. The phytotoxicity test on tomato cuttings proved positive at 2 µg/mL, and in vitro cytotoxic activity assays showed that it inhibited HeLa, KB, and P388/S with ID 50 values of 850, 0.95, and l.00 ng/mL [15].

Metabolites with Enzyme Inhibitory Activity from Paecilomyces
Paecilopeptin (76) is a novel cathepsin S inhibitor produced by P. carneus, which inhibits human cathepsin S in vitro with an IC 50 value of 2.1 nM [60]. A series of inhibitors of the protein tyrosine kinases paeciloquinone A (77), C (78), and D (79) were obtained from P. carneus P-177 [61,62]. Paeciloquinone A (77) and C (78) are potent and selective inhibitors of the v-abl protein tyrosine kinase with an IC 50 value of 0.4 µM [61]. Paeciloquinone D (79) is a protein kinase C inhibitor with an IC 50 value around 6 µM [63].
The metabolite paecilodepsipeptide A (37) was obtained from P. cinnamomeus BCC 9616. It possesses three D-amino acid residues and can act against the malarial parasite Plasmodium falciparum K1, with an IC 50 value of 4.9 µM [4,40]. The compound harzialactone A (99) was isolated from the marine-derived fungus Paecilomyces sp. 7A22. It exhibited significant activity against Leishmania amazonensis with an IC 50 value of 5.25 mg/mL and a moderate activity against intracellular amastigotes with an IC 50 value of 18.18 mg/mL [77].

Conclusions
Since Paecilomyces were first described, many have been proven to be insect pathogens. As a result of the hardiness, wide adaptability, and ease of culture of most species of Paecilomyces, they play an important role in pest control, medicine, functional foods, environmental pollution control, and genetic engineering. Furthermore, Paecilomyces species are a source of bioactive natural products. At present, more than two hundred metabolites have been isolated and identified from Paecilomyces. In this paper, 223 metabolites produced from 13 species and various unidentified species of Paecilomyces were reviewed.
The structures of metabolites from Paecilomyces vary and have been reported ranging from polyketide, terpenoid, peptide, alkaloid, quinone, pyrone, sterol, fatty acid, xanthone, macrocyclic, pyrenocine analog, to radicicol-type forms. The representative secondary metabolites are the highly toxic linear peptides known as leucinostatins, the tyrosine kinase inhibitors paeciloquinones, the tetramic acid derivative, paecilosetin, and a series of trichothecanes. These metabolites have diverse biological activities, such as antimicrobial, antiviral, antitumor, herbicidal, insecticidal, antiplasmodial, antitrypanosomal, nematicidal, cytotoxic, enzyme inhibitors, phytotoxicity, and radical scavenging. The control effect of Paecilomyces is mainly the result of insecticidal activity of its metabolites. Many Paecilomyces metabolites not only directly cause disease in insects, but also have indirect insecticidal effect. For example, the fermentation filtrate of P. lilacinus showed obvious avoidance of soybean cyst nematode larvae and noticeably inhibited the infection of nematodes in roots [93].
In summary, Paecilomyces is a type of fungi with huge potential for development in various applications. With further study, Paecilomyces will play an increasingly important role in biological control, medicine and environmental protection.