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.

1. 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].

Paecilomyces is closely related to all aspects of human life and it plays an irreplaceable role in biological control, and has an important role in medicine and health. This review presents 223 secondary metabolites and their biological activities isolated from the 13 known species and various unidentified strains of Paecilomyces. The review covers reports from 1972 until the present. The structures of all compounds are summarized in Figures 1–3, and the active metabolites are concluded in Table 1.

2. Secondary Metabolites from Paecilomyces

2.1. Metabolites Derived from Paecilomyces with Antimicrobial Activity

Diketopiperazine terezine D (1) (Figure 1 and Table 1) was isolated from P. cinnamomeus BCC 9616, which was firstly found from the coprophilous fungus Spwormiella teretispora. It demonstrated activity against Sordaria fimicola (NRRL6459), causing a 50% reduction in the radial growth rate at 200 μg/disk [4,5]. A maleimide-bearing compound, farinomalein (2), was isolated from P. farinosus HF599, which showed potent activity against the plant pathogen Phytophthora sojae P6497 at 5 µg/disk [6]. α-Pyrone analogue phomaligol A (3) was identified from a strain of P. lilacinus derived from the marine sponge Petrosia sp. [7]. In addition, phomaligol A (3) was also obtained from the marine derived fungus Aspergillus flavus [8] and the blackleg fungus Leptosphaeria maculans [9], and exhibited antibacterial activity against Staphylococcus aureus, methicillin-resistant S. aureus, and multidrug-resistant S. aureus with minimum inhibitory concentration (MIC) values at 31.2–62.5 μg/mL [8]. The complex antibiotic, leucinostatin, was isolated from P. lilacinus A-267 [10], before being separated into leucinostatin A (4) and leucinostatin B (5). They demonstrated antimicrobial activity against bacteria and fungi [11,12]. The compound phomapyrone C (6) was identified from a strain of P. lilacinus [7] and Aspergillus sp. SCSIO 41024 isolated from deep-sea [13]. It had weak antibacterial activity against Acinetobacter baumannii with the MIC value of 250 μg/mL [13].

Figure 1

The structures of metabolites produced by Paecilomyces (1).

Table 1

The active metabolites derived from Paecilomyces.

Metabolites	Paecilomyces Strain	Biological Activities	References
terezine D (1)	P. cinnamomeus BCC 9616	antifungal	[4]
farinomalein (2)	P. farinosus HF599	antifungal	[6]
phomaligol A (3)	P. lilacinus	antibacterial	[7,8]
leucinostatin A (4)	P. lilacinus A-267	antimicrobial, antitumor, uncoupling effect on rat liver mitochondrial function	[10,11,12]
leucinostatin B (5)	P. lilacinus A-267	antimicrobial, antitumor, uncoupling effect on rat liver mitochondrial function	[10,11,12]
phomapyrone C (6)	P. lilacinus	antibacterial	[7,13]
leucinostatin D (7)	P. marquandii	antimicrobial, cytotoxic, phytotoxicity	[15]
leucinostatin H (8)	P. marquandii	antimicrobial	[16]
leucinostatin K (9)	P. marquandii	antimicrobial	[16]
sorbicillinoid (10)	P. marquandii	antibacterial	[17]
beauvericin (11)	P. tenuipes BCC 1614	antimicrobial, cytotoxic, insecticidal	[18]
beauvericin A (12)	P. tenuipes BCC 1614	antimicrobial, cytotoxic, insecticidal	[18]
paecilocin B (13)	P. variotii	antibacterial	[23]
paecilocin C (14)	P. variotii	antibacterial	[23]
semi-viriditoxin (15)	P. varioti	antibacterial	[24]
semi-viriditoxic acid (16)	P. varioti	antibacterial	[24]
lawsozaheer (17)	P. varioti	antibacterial	[25]
varioloid A (18)	P. variotii EN-291	antifungal	[26]
varioloid B (19)	P. variotii EN-291	Antifungal, cytotoxic	[26]
paeciloketal A (20)	P. variotii J08NF-1	antibacterial	[27]
paecilospirone (21)	Paecilomyces sp.	antibacterial	[28]
paeciloxocin A (22)	Paecilomyces sp.	antifungal, cytotoxic	[29]
paecilomycin M (23)	Paecilomyces sp. SC0924	antifungal	[31]
monocillin VI (24)	Paecilomyces sp. SC0924	antifungal	[32]
monocillin VII (25)	Paecilomyces sp. SC0924	antifungal	[32]
aigilomycin B (26)	Paecilomyces sp. SC0924	antifungal	[30]
aigilomycin C (27)	Paecilomyces sp. SC0924	antifungal	[30]
aigilomycin D (28)	Paecilomyces sp. SC0924	antifungal	[30]
1′,2′-epoxy aigialomycin D (29)	Paecilomyces sp. SC0924	antifungal	[30]
LL-Z1640-1 (30)	Paecilomyces sp. SC0924	antifungal	[30]
monocillin II (31)	Paecilomyces sp. SC0924	antibacterial	[33]
monocillin IV (32)	Paecilomyces sp. SC0924	antibacterial	[33]
monorden D (33)	Paecilomyces sp. SC0924	antibacterial	[33]
paeciloside A (34)	Paecilomyces sp. CAFT156	antibacterial, cytotoxic	[38]
acremoauxin A (35)	Paecilomyces sp. CAFT156	antibacterial, cytotoxic	[38]
paeciloxanthone (36)	Paecilomyces sp. (tree 1–7)	antimicrobial, cytotoxic, enzyme inhibition	[39]
paecilodepsipeptide A (37)	P. cinnamomeus BCC 9616	cytotoxic, enzyme inhibition, antimalarial	[40]
farinosone A (38)	P. farinosus RCEF 0101	induce neurite outgrowth in the PC-12 cell line	[41]
farinosone B (39)	P. farinosus RCEF 0101	cytotoxic	[41,42]
farinosone C (40)	P. farinosus RCEF 0101	induce neurite outgrowth in the PC-12 cell line	[41]
paecilosetin (41)	P. farinosus	cytotoxic	[42]
(+)-N-deoxymilitarinone A (42)	P. farinosus RCEF 0097	cytotoxic, induce neurite sprouting in PC-12 cell line	[43]
(3S,6S)-3,6-dibenzylpiperazine-2,5-dione (43)	P. formous 17D47-2	cytotoxic	[44]
gunnilactam A (44)	P. gunnii	cytotoxic	[45]
1,2-dilinolylglycero-O-4′-(N,N,N-trimethyl) homoserine (45)	P. lilacinus ZBY-1	cytotoxic	[46]
methyl myristate (46)	P. lilacinus ZBY-1	cytotoxic	[46]
cerebroside B (47)	P. lilacinus ZBY-1	cytotoxic	[47]
cerebroside C (48)	P. lilacinus ZBY-1	cytotoxic	[47]
cerebroside D (49)	P. lilacinus ZBY-1	cytotoxic	[47]
militarinone A (50)	P. militaris	neurotrophic effect in PC-12 cells	[49]
militarinone B (51)	P. militarisP. farinosus RCEF 0097	cytotoxic	[43,48]
militarinone D (52)	P. militarisP. farinosus RCEF 0097	cytotoxic	[43,48]
(3S)-6-phenethyl-3-isopropyl-1-methyl-2,5-diketopiperazine (53)	P. tenuipes	cytotoxic	[50]
indolyl-6,10b-dihydro-5aH-[1]benzofuro[2,3-b]indole derivative (54)	P. variotii EN-291	cytotoxic	[51]
dihydrocarneamide A (55)	P. variotii EN-291	cytotoxic	[52]
iso-notoamide B (56)	P. variotii EN-291	cytotoxic	[52]
UCE1022 (57)	Paecilomyces sp.	cytotoxic	[53]
saintopin (58)	Paecilomyces sp.	cytotoxic	[54]
paecilomycin P (59)	Paecilomyces sp. SC0924	cytotoxic	[32]
monocillin VI (60)	Paecilomyces sp. SC0924	cytotoxic	[32]
monocillin VII (61)	Paecilomyces sp. SC0924	cytotoxic	[32]
5α,6α-epoxy-(22E,24R)-ergosta-8,22-diene-3β,7α-diol (62)	Paecilomyces sp. J300	cytotoxic	[55]
ergosta-4,6,8(14),22-tetraene-3-one (63)	Paecilomyces sp. J300	cytotoxic	[55]
3β,5α-dihydroxy-6β-methoxyer-gosta-7,22-diene (64)	Paecilomyces sp. J300	cytotoxic	[55]
ergosterol (65)	Paecilomyces sp. J300	cytotoxic	[55]
ergosterol endoperoxide (66)	Paecilomyces sp. J300	cytotoxic	[55]
paecilin A (67)	Paecilomyces sp. (tree 1–7)	cytotoxic	[56]
secalonic acid D (68)	Paecilomyces sp. (tree 1–7)	cytotoxic, enzyme inhibition	[57]
secalonic acid A (69)	Paecilomyces sp. (tree 1–7)	cytotoxic	[58]
tenellic acid A (70)	Paecilomyces sp. (tree 1–7)	cytotoxic	[58]
tetracenomycin D (71)	Paecilomyces sp. (tree 1–7)	cytotoxic	[59]
physcioin (72)	Paecilomyces sp. (tree 1–7)	cytotoxic	[59]
emodin (73)	Paecilomyces sp. (tree 1–7)	cytotoxic	[59]
chrysophanol (74)	Paecilomyces sp. (tree 1–7)	cytotoxic	[59]
1,4-dihydroxy-2-methy anthraquinone (75)	Paecilomyces sp. (tree 1–7)	cytotoxic	[59]
paecilopeptin (76)	P. carneus	inhibiting human cathepsin S	[60]
paeciloquinone A (77)	P. carneus P-177	enzyme inhibition	[61]
paeciloquinone C (78)	P. carneus P-177	enzyme inhibition	[61]
paeciloquinone D (79)	P. carneus P-177	enzyme inhibition	[63]
YW3548 (80)	P. formosus LHL10	enzyme inhibition	[64]
paecilomycone A (81)	P. gunnii	enzyme inhibition	[65]
paecilomycone B (82)	P. gunnii	enzyme inhibition	[65]
paecilomycone C (83)	P. gunnii	enzyme inhibition	[65]
paecilomide (84)	P. lilacinus	enzyme inhibition	[66]
Sphingofungin E (85)	P. variotii ATCC 74097	enzyme inhibition	[67]
Sphingofungin F (86)	P. variotii ATCC 74097	enzyme inhibition	[67]
verticilatin (87)	P. verticillatus	enzyme inhibition	[68]
3α-hydroxy-3,5-dihydro ML-236C (88)	P. viridis L-68	enzyme inhibition	[69]
12-hydroxyalbrassitriol (89)	Paecilomyces sp. TE-540	enzyme inhibition	[70]
2-hydroxyalbrassitriol (90)	Paecilomyces sp. TE-540	enzyme inhibition	[70]
phenopicolinic acid (91)	Paecilomyces sp. AF2562	enzyme inhibition	[71]
kurasoin A (92)	Paecilomyces sp. FO-3684	enzyme inhibition	[72]
kurasoin B (93)	Paecilomyces sp. FO-3684	enzyme inhibition	[72]
catenioblin C (94)	P. cateniobliquus YMF1.01799	promoted the growth of the larvae of cotton bollworm	[73]
phomalactone (95)	P. cateniobliquus YMF1.01799	inhibition cotton bollworm	[73]
cerebrosides A (96)	P. lilacinus ZBY-1	nematicidal	[74]
4-(4′-carboxy-2′-ethyl-hydroxypentyl)-5,6-dihydro-6-methyl-cyclobut[b]pyridine-3,6-dicarboxylic acid (97)	Paecilomyces sp. YMF1.01761	nematicidal	[75]
paeciloxazine (98)	Paecilomyces sp. BAUA3058	Nematicidal, insecticidal	[76]
harzialactone A (99)	Paecilomyces sp. 7A22	insecticidal	[77]
paecilomycin E (100)	Paecilomyces sp. SC0924	antiplasmodial	[78]
paecilomycin F (101)	Paecilomyces sp. SC0924	antiplasmodial	[78]
aigilomycin B (102)	Paecilomyces sp. SC0924	antiplasmodial	[78]
aigialomycin F (103)	Paecilomyces sp. SC0924	antiplasmodial	[78]
pyrenocine I (104)	Paecilomyces sp. FKI-3573	antitrypanosomal	[79]
pyrenocine A (105)	Paecilomyces sp. FKI-3573	antitrypanosomal	[79]
pyrenocine B (106)	Paecilomyces sp. FKI-3573	antitrypanosomal	[79]
citreoviridin (107)	Paecilomyces sp. FKI-3573	antitrypanosomal	[79]
spirotenuipesine A (108)	P. tenuipes	activity in neurotrophic factor biosynthesis in glial cells	[81]
spirotenuipesine B (109)	P. tenuipes	activity in neurotrophic factor biosynthesis in glial cells	[81]
paecilomycine A (110)	P. tenuipes	activity in neurotrophic factor biosynthesis in glial cells	[80]
formoxazine (111)	P. formosus	radical-scavenging activity	[82]
terreusinone (112)	P. formosus	UV-A absorbing activity	[83]
3-[(2Z)-1-oxo-2-buten-1-yl]oxazolidin-2-one (113)	P. formosus	radical-scavenging activity	[82]
14-hydroxycornexistin (114)	P. variotii	herbicidal	[84]
cornexistin (115)	P. variotii SANK 21086	herbicidal	[85,86]

A series of peptidic antibiotics: leucinostatin A (4), D (7), H (8), and K (9), were identified from P. marquandii [14,15,16]. Leucinostatin D (7) showed biological activities against Gram-positive bacteria and several fungi, for example, Bacillus subtilis ICI, Micrococcus luteus ISS, Streptococcus pneumonia, S. haemolyticus, and S. aureus [15]. Leucinostatin H (8) and K (9) also exhibited activities against Gram-positive bacteria and fungi, but the antibacterial and the antimycotic activity reduce significantly upon N-oxidation [16]. A Diels-Alder product of sorbicillinoid (10) with a urea group was isolated from P. marquandii, a intertidal marine strain, which had antibacterial activity against B. subtilis ATCC 6633 and E. coli ATCC 25922 [17].

Cyclodepsipeptides beauvericin (11) and beauvericin A (12) were isolated from P. tenuipes BCC 1614. The two compounds displayed antimicrobial activities [18]. Beauvericin (11) can also be obtained from several fungi, including Beauveria bassiana, Polyporus sulphureus, and Fusarium spp. [19,20,21,22].

Two polyketides paecilocin B (13) and C (14) were identified from P. variotii derived from the jellyfish Nemopilema nomurai, which showed moderate antibacterial activity against S. aureus SG 511 and MRSA 3089 with MIC values ranging from 5 to 40 μg/mL [23]. Two metabolites, semi-viriditoxin (15) and semi-viriditoxic acid (16), were produced by a strain of P. variotii, isolated from the larvae of Dendroctonus ponderosa, and the two metabolites (15, 16) showed weak antibacterial activity against a number of bacteria [24]. One chromone, lawsozaheer (17) was isolated from the broth of Paecilomyces variotii. It demonstrated highly selective activity against S. aureus (NCTC 6571) with 84.26% inhibition at 150 μg/mL [25]. Two oxepine-containing diketopiperazine-type alkaloids, varioloid A (18) and B (19), were identified from the marine alga-derived P. variotii EN-291, exhibiting potent activity against the plant pathogenic fungus Fusarium graminearum with MIC values of 8 and 4 mg/mL, respectively [26]. A benzannulated spiroketal derivative, paeciloketal A (20), was obtained from P. variotii J08NF-1, a jellyfish-derived strain, which showed antibacterial activity with a MIC value of 40 μg/mL against the marine pathogen Vibrio ichthyoenteri [27].

A metabolite paecilospirone (21), was reported from Paecilomyces sp., with a MIC value of 5 μg/mL against B. subtilis at 25 °C; however, at 37 °C, it did not show any antimicrobial activity [28]. Paeciloxocin A (22) was isolated from Paecilomyces sp., and it inhibited the growth of Curvularia lunata and Candida albicans ATCC 10231 with inhibition zones of 12 and 10 mm, respectively [29]. Paecilomycin M (23), monocillin VI (24) and VII (25), aigilomycin B–D (26–28), 1′,2′-epoxy aigialomycin D (29), LL-Z1640-1 (30), monocillin II (31), monocillin IV (32), and monorden D (33) were produced by Paecilomyces sp. SC0924. Compounds 23–30 exhibited weak antifungal activity against Peronophythora litchi [30,31,32]. Metabolites 31–33 can be separated from Pochonia chlamydosporia and demonstrated modest activity against Xanthomonas campestris, with a MIC value of 25.6 μg/mL [33]. Aigialomycin-type compound was also reported to be derived from Aigialus parvus [34,35]. LL-Z1640-1 (30) was firstly isolated from an unidentified fungus [36] and was also obtained from the gorgonian derived fungus Cochliobolus lunatus [37].

The antimicrobial and cytotoxic polyketide paeciloside A (34) and the compound acremoauxin A (35) were identified from a strain of Paecilomyces sp. CAFT156 [38]. Compounds 34 and 35 displayed inhibitory effects on two bacteria B. subtilis and S. aureus at 40 μg/disk [38]. A metabolite, paeciloxanthone (36), was obtained from Paecilomyces sp. (tree 1–7), a strain isolated from an estuarine mangrove from the Taiwan Strait. Metabolite 36 is active against C. lunata, E. coli., and C. albicans at 40 μg/disk, producing inhibitory zones of 6, 12, and 10 mm, respectively [39].

2.2. Cytotoxic Metabolites Derived from Paecilomyces

An antitumor cyclohexadepsipeptide, paecilodepsipeptide A (37), was derived from P. cinnamomeus BCC 9616. Paecilodepsipeptide A (37) exhibits cytotoxicity against cancer cell lines, KB and BC, with IC50 (the half maximal inhibitory concentration) values of 5.9 and 6.6 µM, respectively [40].

Farinosone A–C (38–40), three neurotrophic alkaloidal metabolites produced by P. farinosus RCEF 0101. Farinosone A (38) and C (40) can induce neurite outgrowth in the PC-12 cell line at concentrations of 50 µM, while farinosone B is inactive [41]. A tetramic acid derivative, paecilosetin (41), along with farinosone B (39), was isolated from P. farinosus. The two metabolites showed activity against the P388 cell line with IC50 values of 3.1 and 1.1 µg/mL, respectively [42]. A pyridone alkaloid, (+)-N-deoxymilitarinone A (42), was obtained from a strain of P. farinosus RCEF 0097. Compound 42 induced neurite sprouting in the PC-12 cell line when tested at concentrations of 33 and 100 µM and a cytotoxic effect was observed in human neurons (IMR-32) at 100 µM [43]. The metabolite (3S,6S)-3,6-dibenzylpiperazine-2,5-dione (43) was isolated from a culture extract of marine-derived P. formous 17D47-2; it showed selective cytotoxic activity in human pancreatic carcinoma PANC-1 cells adapted to glucose-starved conditions, with an IC50 value of 28 µM, whereas no effect against PANC-1 cells under general culture conditions up to 1000 µM [44].

A novel macrocyclic, tetralactams gunnilactam A (44), isolated from P. gunnii, exhibited cytotoxic activity against human prostate cancer C42B cells with an IC50 value of 5.4 μM [45].

A series of metaboilites, including 1,2-dilinolylglycero-O-4′-(N,N,N-trimethyl) homoserine (45), methyl myristate (46) [46] and cerebroside B–D (47–49) [47], were isolated from marine-derived P. lilacinus ZBY-1. The metabolites 45 and 46 inhibited the human cancer K562, MCF-7, HL-60, and BGC-823 cells lines with the IC50 values ranging from 1.12 to 8.63 μmol/L [46]. The compounds cerebroside B–D (47–49) inhibited K562, MCF-7, HL-60, and BGC-823 cells with IC50 values ranging from 9.5 to 59.6 mg/L [47]. Leucinostatin A (4) and B (5), derived from P. lilacinus A-267, as well as having antimicrobial activity, also showed antitumor activity and an uncoupling effect on rat liver mitochondrial function [11,12].

Three novel pyridone alkaloids, militarinone A (50), B (51), and D (52), were isolated from the mycelium of P. militaris [48,49]. Militarinone A (50) had a pronounced neurotrophic effect in the PC-12 cells at concentration of 10 µM [48]. Militarinone D (52) showed significant cytotoxicity against PC-12 cells with 74.0% and 30.7% at concentrations of 100 and 33 µM, respectively, and militarinone B (51) was weakly cytotoxic at 100 µM (16.8%) [49]. In addition, militarinone B (51) and D (52) can also be obtained from a strain of P. farinosus RCEF 0097 [43].

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 ID50 values of 850, 0.95, and l.00 ng/mL [15].

The novel metabolite (3S)-6-phenethyl-3-isopropyl-1-methyl-2,5-diketopiperazine (53) was obtained from P. tenuipes and showed cytotoxicity against 22RV1 and DU-145 prostate cancer cells with inhibition rates of 37.8% and 38.6% at 5 µm/L [50]. Cyclodepsipeptide beauvericin (11) and beauvericin A (12) derived from P. tenuipes BCC 1614 also showed cytotoxic activity [18].

A series of compounds, including a indolyl-6,10b-dihydro-5aH-[1]benzofuro[2,3-b]indole derivative (54), a diketopiperazine-type alkaloid varioloid B (19), and two prenylated indole alkaloids dihydrocarneamide A (55), and iso-notoamide B (56), were identified from the marine alga-derived P. variotii EN-291 [26,51,52]. Compounds 19 and 54 exhibited cytotoxicity against A549, HCT116, and HepG2 cell lines, with IC50 values from 2.6 to 8.2 µg/mL [51]. Dihydrocarneamide A (55) and iso-notoamide B (56) showed cytotoxic activities against NCI-H460 with IC50 values of 69.3 and 55.9 mmol/L, respectively [52].

Three metabolites, UCE1022 (57), saintopin (58), and paeciloxocin A (22), were identified from an unidentified species of Paecilomyces. UCE1022 (57) displayed in vitro cytotoxic activity against HeLa S3 at IC50 6.1 μM [53]. Saintopin (58) shows in vitro cytotoxic activity against HeLa S3 at IC50 0.35 μg/mL, and further demonstrated in vivo antitumor activity against murine leukemia P388 (ip) [54]. Paeciloxocin A (22) exhibited significant cytotoxicity against hepG2 with an IC50 value of 1 μg/mL [29]. A β-resorcylic acid lactone, paecilomycin P (59), and two radicicol-type metabolites, monocillin VI and VII (60, 61) were produced by a strain of Paecilomyces sp. SC0924 [32]. The three compounds (59–61) exhibited cytotoxicity against MCF-7, A549, and HeLa cells [32]. The metabolites paeciloside A (34) and acremoauxin A (35) were identified from Paecilomyces sp. CAFT156. The two compounds displayed moderate cytotoxicity towards Artemia salina [38]. The cytotoxic ergosterols, including 5α,6α-epoxy-(22E,24R)-ergosta-8,22-diene-3β,7α-diol (62), ergosta-4,6,8(14),22-tetraene-3-one (63), 3β,5α-dihydroxy-6β-methoxyer-gosta-7,22-diene (64), ergosterol (65), and ergosterol endoperoxide (66), were produced by Paecilomyces sp. J300 [55]. These compounds showed moderate cytotoxicity against A549, SK-OV-3, SK-MEL-2, XF498 (CNS), and HCT15 cells [55]. A sequence of metabolites, including paeciloxanthone (36) [39], paecilin A (67), secalonic acid D (68), secalonic acid A (69), tenellic acid A (70), and five anthraquinone derivates, tetracenomycin D (71), physcioin (72), emodin (73), chrysophanol (74), 1,4-dihydroxy-2-methy anthraquinone (75) were obtained from Paecilomyces sp. (tree 1–7) [39,56,57,58]. Paeciloxanthone (36) exhibited in vitro cytotoxicity against hepG2 with an IC50 value of 1.08 μg/mL [39]. Paecilin A (67) showed inhibiting activity against KB and KBv cells with IC50 values of 40 and 50 nmol/mL, respectively [56]. Secalonic acid D (68) showed cytotoxicity towards KB cells with an value of IC50 < 1 µg/mL and inhibited human topoisomerase I with an IC50 value of 0.16 µmol/mL [57]. Secalonic acid A (69) (Figure 2) and tenellic acid A (70) inhibited the growth of the human hepatoma cell line HepG2, with IC50 values of 62.1 and 2.0 μg/mL, respectively [58]. Compounds 71–75 showed anticancer activity against KB and KBv, with IC50 values of 11, 20, 8, 15, and 18 μmg/mL and 17, 30, 10, 20, and 25 μmg/mL, respectively [59].

Figure 2

The structures of metabolites produced by Paecilomyces (2).

2.3. 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 IC50 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 IC50 value of 0.4 μM [61]. Paeciloquinone D (79) is a protein kinase C inhibitor with an IC50 value around 6 μM [63].

Two metabolites, sester-terpenoid YW3548 (80) and a cyclic peptide paecilodepsipeptide A (37), were isolated from endophytic P. formosus LHL10 [64]. The two compounds exhibited remarkable inhibitory rates against α-glucosidase and urease, with IC50 values of 61.80 ± 5.7 and 75.68 ± 6.2, and 74.25 ± 4.3 and 190.5 ± 10.31 µg/g, respectively [64], which were also obtained from P. cinnamomeus [40]. Paecilomycone A–C (81–83) were identified from P. gunnii with IC50 values of 0.11, 0.17, and 0.14 mM on Tyrosinase, respectively [65]. A pyridone alkaloid, paecilomide (84), derived from P. lilacinus, demonstrated an acetylcholinesterase inhibition of 57.5 ± 5.50% [66].

Sphingofungins E (85) and F (86) are novel structures in the sphingofungin family which can inhibit serinepalmitoyl transferase at nanomolar levels; the estimated IC50 values were 7.2 and 57 nM, respectively, which were obtained from a strain of P. variotii ATCC 74097 [67]. A oxybis cresol, verticilatin (87), was identified from cultures of P. verticillatus. Verticilatin (87) exhibited significant inhibitory activity against CDC25B, cathepsin B, MEG2, and SHP2 enzyme, with IC50 values of 11.5, 3.5, 7.8, and 15 μg/mL, respectively [68]. A metabolite of the compactin family, 3α-hydroxy-3,5-dihydro ML-236C (88), was isolated from P. viridis L-68, and the in vitro activity of HMG-CoA reductase was inhibited by approximately 50% by this compound 88 [69].

The cadinane-type sesquiterpenoid analogs, 12-hydroxyalbrassitriol (89) and 2-hydroxyalbrassitriol (90), were obtained from the endophytic fungus Paecilomyces sp. TE-540. The two compounds showed moderate activities against acetylcholinesterase (AChE), with IC50 values of 43.02 ± 6.01 and 35.97 ± 2.12 μM, respectively [70]. Phenopicolinic acid (91), a potent inhibitor of dopamine β-hydroxylase, was found in culture filtrates of Paecilomyces sp. AF2562. The LD50 (median lethal dose or concentration) of phenopicolinic acid (91) for mice was about 350 mg/kg through intraperitoneal injection [71].

Two novel protein farnesyltransferase (PFTase) inhibitors, kurasoin A (92) and B (93), were derived from the cultured broth of Paecilomyces sp. FO-3684 [72]. The two metabolites inhibited PFTase in a dose-dependent, with IC50 values of 59.0 and 58.7 μM, respectively [72]. The metabolites paeciloxanthone (36) and secalonic acid D (68) were isolated from Paecilomyces sp. (tree 1–7). Paeciloxanthone (36) exhibited in vitro AChE inhibition with an IC50 value of 2.25 μg/mL [39], and secalonic acid D (68) inhibited human topoisomerase I with an IC50 value of 0.16 µmol/mL [57].

2.4. Insecticidal, Nematicidal, Antiplasmodial, and Antimalarial Metabolites Derived from Paecilomyces

Catenioblin C (94) and phomalactone (95) were identified from P. cateniobliquus YMF1.01799 [73]. The polyketide-derived phomalactone (95) had a significant inhibitory effect on the growth of the cotton bollworm Helicoverpa armigera, while the terpenoid derived metabolite catenioblin C (94) promoted the growth of the larvae [73]. Beauvericin (11) and beauvericin A (12) with diversiform bioactivities obtained from P. tenuipes BCC 1614, also demonstrated promising insecticidal activity [18]. The metabolite cerebrosides A (96) was isolated from marine-derived P. lilacinus ZBY-1, and its nematicidal activity against Bursaphelenchus xylophilus was investigated. The result showed that the average mortality of B. xylophilus treated with cerebroside A (96) at the mass concentrations of 1000, 100, and 10 μg/mL were 100%, 100%, and 11.1%, respectively [74].

A nematicidal metabolite 4-(4′-carboxy-2′-ethyl-hydroxypentyl)-5,6-dihydro-6-methyl- cyclobut[b]pyridine-3,6-dicarboxylic acid (97), was produced by Paecilomyces sp.YMF1.01761. Within 24 h, the LD50 value was 50.86 mg/L against Panagrellus redivivus, 47.1 mg/L against Meloidogyne incognita, and 167.7 mg/L against B. xylophilus [75]. Paeciloxazine (98) was isolated from Paecilomyces sp. BAUA3058, demonstrating moderate nematicidal activity against Rhabditis pseudoelongata and weak activity against some insects [76].

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 IC50 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 IC50 value of 5.25 mg/mL and a moderate activity against intracellular amastigotes with an IC50 value of 18.18 mg/mL [77].

Two novel β-resorcylic acid lactones, paecilomycin E, F (100, 101), along with aigilomycin B (102) and aigialomycin F (103) were isolated from a strain of Paecilomyces sp. SC0924 [78]. Paecilomycin E (100) and aigialomycin F (103) exhibited antiplasmodial activity against the Plasmodium falciparum line 3D7 with IC50 values of 20.0 and 10.9 nM, respectively, and paecilomycin E, F (100, 101) and aigilomycin B (102) showed moderate activity against the P. falciparum line Dd2 [78]. Four metabolites containing pyrenocine I (104), pyrenocine A, B (105, 106) and citreoviridin (107) were produced by Paecilomyces sp. FKI-3573 [79]. These compounds exhibit in vitro antitrypanosomal activity, and pyrenocine A (105) showed the most potent activity with an IC50 value of 0.12 mg/mL [79].

2.5. Other Active Metabolites Derived from Paecilomyces

The metabolites spirotenuipesine A, B (108, 109) and paecilomycine A (110) were obtained from P. tenuipes. The three compounds showed potent activity in neurotrophic factor biosynthesis in glial cells [80,81]. A pyrrolooxazine, formoxazine (111), a dipyrroloquinone derivative, terreusinone (112), and a 2-oxazolidinone analogue, 3-[(2Z)-1-oxo-2-buten-1-yl]oxazolidin-2-one (113) were isolated from the marine-derived P. formosus [82]. The compounds 111 and 113 displayed potent radical-scavenging activity against DPPH, with IC50 values of 0.1 and 10 μM [82]. Terreusinone (112) exhibited a UV-A absorbing activity with an ED50 value of 70 µg/mL [83]. Phytotoxin 14-hydroxycornexistin (114), a member of the nonadride family, was obtained from P. variotii, exhibiting a potent activity against broadleaf weeds and a selectivity to corn [84]. A herbicidal antibiotic, cornexistin (115), was isolated from P. variotii SANK 21086, which shows non-selective, broad spectrum herbicidal activity against annual plants including mono- and dicotyledonous weeds and may be useful for postemergence weed control with selective protection of corn [85,86]. In addition, cornexistin (115) was also isolated from P. tenuipes [25].

2.6. Metabolites with Unknown Activity Derived from Paecilomyces

The metabolites paeciloquinone B (116) and paeciloquinone E, F (117, 118) were obtained from P. carneus P-177 [61,62]. Two compounds, catenioblin A, B (119, 120) were identified from P. cateniobliquus YMF1.01799 for the first time [73]. The metabolites paecilodepsipeptide B and C (121, 122), a xanthone glycoside, norlichexanthone-6-O-(4-O-methylglucopyranoside) (123), and hopane triterpene zeorin (124) were produced by P. cinnamomeus BCC 9616 [4,40]. Two novel macrocyclic tetralactams, gunnilactam B, C (125, 126) were produced by P. gunnii [45].

A series of compounds, including two α-pyrones, paecilopyrone A, B (127, 128); two cyclohexenones, phomaligol B, C (129, 130); and the analogues, phomapyrone B (131) and C (6), kojic acid (132), phomaligol A (3), methylphomaligol A (133), phomaligol A1 (134), acetylphomaligol A (135), phomaligol A hydroperoxide (136), and phomaligol A1 hydroperoxide (137), were identified from a strain of P. lilacinus derived from the marine sponge Petrosia sp. The compounds kojic acid (132), phomaligol A (3), and methylphomaligol A (133) were evaluated for their cytotoxicity against a small panel of human solid tumor cell lines and were found to be inactive up to a concentration of 30 µg/mL [7]. In addition, phomaligol A1 (134) can also be obtained from the blackleg fungus L. maculans [9]. Eleven metabolites, including paecilaminol (138), paecilaminol hydrochlorate (139), methyl linoleate (140), linoleate (141), oleinic acid (142), indole-3-carboxaldehyde (143), indolyl-3-carboxylic acid (144), 4-hydroxybenzoic acid (145), 9(11)-dehydroergosterol peroxide (146), (22E,24R)-5α,6α-epoxy-3β-hydroxyergosta-22-ene-7-one (147), and ergosterol peroxiden (148) were isolated from marine derived P. lilacinus ZBY-1 [46,47].

A novel pyridone alkaloid, militarinone C (149), was obtained from the mycelium of P. militaris [49]. Six secondary metabolites were obtained from P. tenuipes, which include (4S,10R)-4-hydroxy-8-oxygen-10-methyl solactone (150), tenuipesine A (151), paecilomycines B, C (152, 153), cepharosporolide C (154) (Figure 3) and E (155) [50,80,87]. Paecilocin A (156) and D (157), 4-(2-hydroxyethyl) phenol (158), stigmasta 4,6,8(14),22-tetraen-3-one, β-sitosterol (159) and stigmasterol (160) were reported from P. variotii [23,25]. Two bicyclic fatty acids, paecilonic acid A (161) and B (162), together with two benzannulated spiroketal derivatives, paeciloketal B (163) and 1-epi-paeciloketal B (164) were obtained from jellyfish-derived strain of P. variotii J08NF-1 [27,88]. The metabolites 5-methylresorcinol (165) and 2,4-dihydroxy-3,6-dimethylbenzaldehyde (166) were isolated from cultures of P. verticillatus [68].

Figure 3

The structures of metabolites produced by Paecilomyces (3).

Two novel unique spiro[chroman-2,1′(3′H)-isobenzofuran] derivative (167), (3R*,5E, 7E,9R*,11E,13Z)-1-((3′aS*,6′aR*)-2-amino-5-oxo-3′a,5′,6′,6′α-tetrahydrofu-ro[3′,2-b]furan-3-yl)-3,7,9,11-tetramethylheptadeca-5,7,11,13-tetraene-1,2-dione (168), together with cholesteryl linoleate (169), and 2,5-furandimethanol (170) were isolated from marine-derived strains of Paecilomyces [3,89].

A diterpenoid, paecilomycine B (171), with a five-membered lactone ring, and three labdane diterpenoids, botryosphaerin E (172), agathic acid (173), and rel-(1R,3S,4aS,5R,8aS)-5-[(3E)-4- carboxy-3-methylbut-3-en-1-yl]decahydro-3-hydrxy-1,4a-dimethyl-6-methylidenenaphthalene-1-carboxylic acid (174) were identified from the solid culture of Paecilomyces sp. ACCC 37762 [90]. A number of β-resorcylic acid lactones paecilomycin A–D (175–178), paecilomycin G–L (179–184), paecilomycin N, O (185,186), 4′-hydroxymonocillin IV (187), 4′-methoxymonocillin IV (188), zeaenol (189), aigialospirol (190), zearalenone (191), 7′-dehydrozearalenone (192), trans-7′,8′- dehydrozearalenol (193), monocillin I (194), monocillin Ⅲ (195), radicicol (196), lasicicol (197), and hypothemycin (198) were produced by a strain of Paecilomyces sp. SC0924 [30,31,32,78]. Furthermore, the compound 7′-dehydrozearalenone (192) was firstly isolated from Gibberella zeae [91].

The metabolites 1,5-dideoxy-3-C-methyl-arabitol (199) and adenosine (200) were identified from a strain of Paecilomyces sp. CAFT156 [38]. Several compounds, including a indolinepeptide, 3β,5-dihydroxy-l-N-methyl-indoline-2β-carbonyl amino-d-alanyl-erythro-β-hydoxyisoleucinyl-glycine (201), (4E, 8E, 2S, 2′R, 3R)-N-2′-hydroxy-hexadecanoyl-l-O-β-d-glucopyranosyl-9-methyl-4, 8-sphingadienin (202), alloxazine (203), along with the ergosterol derivatives, 3β,5α-dihydroxy-ergosta-7,22-diene (204), 5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7α-diol (205), were isolated from Paecilomyces sp. J300 [2,55]. Two cadinane-type sesquiterpenoids, paecilacadinol A and B (206, 207), two drimane-type sesquiterpenoids, ustusol D (208) and ustusol E (209), and the four analogs, deoxyuvidin B (210), 3β,9α,11-trihydroxy-6-oxodrim-7-ene (211), 2α,11-dihydroxy-6-ox-odrim-7-ene (212), and ustusol B (213) were obtained from the endophytic fungus Paecilomyces sp. TE-540 [70]. The metabolite, paecilin B (214) [57], and nine cyclic peptides, viscumamide (215), cyclo(Pro-Iso) (216), cyclo(Phe-Gly) (217), cyclo(Phe-Ana) (218), cyclo(Gly-Pro) (219), cyclo(Gly-Leu) (220), cyclo(Trp-Ana) (221), necoeshinulin A (222), and cyclo(Pro-Thr) (223) were identified from Paecilomyces sp. (tree 1–7) [92].

3. 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.