Planta Med 2018; 84(09/10): 594-605
DOI: 10.1055/s-0044-101551
Reviews
Georg Thieme Verlag KG Stuttgart · New York

Insights in Fungal Bioprospecting in Mexico[*]

Rachel Mata
1   Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, México
,
Mario Figueroa
1   Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, México
,
Isabel Rivero-Cruz
1   Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, México
,
Martha L. Macías-Rubalcava
2   Instituto de Química, Departamento de Productos Naturales, Universidad Nacional Autónoma de México, Ciudad de México, México
› Author Affiliations
Further Information

Correspondence

Prof. Dr. Rachel Mata
Departamento de Farmacia
Facultad de Química
Universidad Nacional Autónoma de México
Ciudad de México
México   
Phone: + 52 55 56 22 52 89   
Fax: + 52 55 56 22 53 29   

Publication History

received 21 November 2017
revised 09 January 2018

accepted 17 January 2018

Publication Date:
01 February 2018 (online)

 

Abstract

Fungi have consistently been one of the richest sources of natural products, with unprecedented chemical scaffolds and potent biological activities. During the last 20 years, pharmacognosy researchers in Mexico, in collaboration with mycologists, have discovered many novel bioactive fungi natural products and new fungal species. To date, more than 100 bioactive secondary metabolites from 20 fungi from different ecosystems throughout Mexico have been documented in peer-reviewed literature according to Scopus and SciFinder databases. These include compounds from different biosynthetic origins and structural cores with the potential for the development of anticancer, antidiabetic, and/or pesticide agents.


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Introduction

Fungi represent a prized source of natural product bioactive compounds with an enormous and relevant impact in human medicine and crop protection. Some important drugs and products for agriculture have been derived from or inspired by fungal natural products; some important examples include β-lactam antibiotics, griseofulvin, cyclosporine, statins, echinocandins, PF1022A, nodulisporic acid, scyphostatin, and strobilurins. According to new evidence, the number of fungal species might be between 2.2 and 3.8 million, with 120 000 currently accepted [1]. Since the estimations of fungal biodiversity exceed, by far, the number of already identified species, chances of finding unidentified fungal species and novel bioactive products are still high [2]. Furthermore, the advances in genomic analysis techniques have permitted the discovery of innumerable putative gene clusters for potentially bioactive compounds.

The knowledge of fungal biodiversity in Mexico is still poor. A recent analysis proposed that there are 200 000 fungal species, but only 5% of these have been studied [3]. Consequently, the potential of fungal biodiversity from Mexico as a source of bioactive compounds remains largely unexplored. Thus, the aim of this paper is to provide an overview on the status of fungal bioprospecting in Mexico in the last two decades, considering only the work pursued in the authors laboratories at the National Autonomous University of Mexico. Twenty fungi have been investigated from the biological and chemical point of view, leading to the isolation of over 100 bioactive secondary metabolites of medicinal and/or agrochemical relevance. This information has been reported in over 50 peer-reviewed publications according to Scopus and SciFinder databases. In the medicinal area, the studies were focused on the discovery of new leads for the development of antitumoral, Ca2+-calmodulin (CaM) antagonists, and antidiabetic drugs with α-glucosidase inhibitory activity. In the field of agrochemicals, the studies emphasized the discovery of potential herbicidal, antifungal, and anti-oomycete agents.

The fungi discussed in this review were isolated from diverse substrates, mainly from plants (endophytes), dung, soil, insects, and marine environments belonging to different ecosystems in Mexico. Bioprospecting of endophytes from wild medicinal plants is a successful strategy for the discovery of novel and known bioactive compounds [4]. Accordingly, we analyzed endophytes from selected medicinal plants, including Hintonia latiflora (Sessé & Moc. ex DC.) Bullock (Rubiaceae), Bursera simaruba (L.) Sarg. (Burseraceae), Callicarpa acuminata Kunth. (Verbenaceae), Haematoxylon brasiletto H. Karst. (Fabaceae), Sapium macrocarpum Muell. Arg. (Euphorbiaceae), and Gliricidia sepium (Jacq.) Kunth ex Walp. (Fabaceae). The endophytic fungi reviewed includes strain MEXU 27095 (Chaetomiaceae), Preussia minimoides (S. I. Ahmed & Cain) Valldos. & Guarro (Sporormiaceae), Xylaria feejeensis (Berk.) Fr. (Xylariaceae), Edenia gomezpompae M. C. González, Anaya, Glenn, Saucedo & Hanlin (Pleosporaceae), Muscodor yucatanensis M. C. González, Anaya, Glenn & Hanlin (Xylariaceae), Acremonium camptosporum W. Gams (Clavicipitaceae), X. feejeensis SM3e-1b, and Hypoxylon anthochroum Berk. & Broome strains Blaci and GS4d2II (Xylariaceae).

Coprophilous fungi are a large group of saprotrophic fungi, which represent an important reservoir of useful novel bioactive secondary metabolites. The number of dung fungi undergoing investigation is continuously increasing with new species and genera constantly described [5], [6]. On these grounds, a few coprophilous fungi isolated from bat dung in different regions of Mexico have been investigated in our laboratories. Some of these fungi include Penicillium spathulatum B35 Frisvad & Samson (Trichocomaceae), Penicillium sp. G1-a14, Guanomyces polythrix M. C. González, Hanlin & Ulloa (Chaetomiaceae), and Malbranchea aurantiaca Sigler and Carmich (Myxotrichaceae).

Marine fungi (sensu stricto) or those isolated from a marine substratum are a rich source of new natural products with interesting chemical scaffolds and potent biological activities [7], therefore Aspergillus stromatoides Raper & Fennell (Trichocomaceae), Aspergillus sp. MEXU 27854, and Emericella sp. MEXU 25379 (Trichocomaceae) were analyzed. Among the entomophatogenic fungi, we have only investigated Isaria fumosorosea Wize (Clavicipitaceae), a fungus currently used for the biological control of whiteflies (Bemisia tabaci Gennadius). Phytopathogenic fungi are known to be involved in several plant diseases that damage agrarian and forest crops, besides having general adverse effects on wild plant species. These damages are produced by toxins which, in many cases, have been used to obtain products for plant protection. Based on this consideration, we investigated Phoma herbarum Westend. (Pleosporales). Finally, two saprophytes were investigated, Malbranchea flavorosea Sigler & J. W. Carmich. (Myxotrichaceae), isolated from soil, and Purpureocillium lilacinum (Thom) Luangsa-ard, Houbraken, Hywel-Jones & Samso (Ophiocordycipitaceae).


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Alpha-Glucosidase Inhibitors

Type II diabetes mellitus is a disease with skyrocketing prevalence. The number of patients today, ~ 380 million, will increase to ~ 450 million in 2030. In this scenario, extraordinary efforts have been made to identify lead compounds for the development of new drugs for treating this disease. Metformin remains the first-line pharmacotherapy for patients with type II diabetes mellitus, whereas the use of other well-established agents, such as sulfonylureas, meglitinides, thiazolidinediones, and α-glucosidase inhibitors, varies in different regions [8]. In areas with a large intake of complex carbohydrates, α-glucosidase inhibitors are widely used. These agents competitively inhibit α-glucosidase enzymes in the brush border of enterocytes lining the intestinal villi. Inhibition of intestinal α-glucosidases delays the digestion of starch and sucrose, flattens the postprandial blood glucose excursions, and thus mimics the effects of dieting on hyperglycemia, hyperinsulinemia, and hypertriglyceridemia [9], [10]. They minimize hypoglycemia and weight gain, increase postprandial glucagon-like peptide-1 secretion, decrease both postprandial hyperglycemia and hyperinsulinemia, and thereby may improve sensitivity to insulin. The α-glucosidase inhibitors class currently comprises three compounds, namely, acarbose, miglitol, and voglibose. Gastrointestinal adverse effects and a rapid absorption rate of some α-glucosidase inhibitors are commonly encountered and can lead to treatment withdrawal.

Based on the above considerations, we have explored a few fungi to discover new α-glucosidase inhibitors. To detect fungi extracts suitable for α-glucosidase inhibitor isolation, first an in vitro enzymatic test is carried out using a well-known spectrophotocolorimetric procedure [11]. Those extracts with evident activity in the assay were subjected to activity-guided fractionation. Once the active compounds are obtained and characterized, if the quantity of the active compounds is sufficient (over 100 mg), animal in vivo studies using an oral sucrose tolerance test in normal and hyperglycemic mice were performed. In most cases, docking studies are performed using protein models of human N-terminal and C-terminal subunits of maltase glucoamylase (hNt-MGAM, PDB code 2QMJ; and hCt-MGAM, PDB code 3TOP; respectively), human N-terminal sucrose isomaltase (hNt-SI, PDB code 3LPP), and yeast isomaltase (y-IM, PDB code 3A4A). Recent work in this area is summarized in the following paragraphs.

Fungal endophytes from Hintonia latiflora

H. latiflora is a Mexican medicinal plant with a long history of use for treating diabetes. Owing to its antidiabetic effect, Mexican and several European drug companies have commercialized herbal products containing the stem bark of this species for decades (e.g., Sucontral D, Copalchi-Bellsolá, Copalchi, Copangel, among others). The plant has been the subject of many chemical and pharmacological studies that have established the hypoglycemic and antihyperglycemic actions. The active principles are a few cucurbitacins and 4-phenylcoumarins type of compounds [12]. With the increasing demand for herbal drugs and natural health products, wild H. latiflora and related species are facing accelerated loss and are now threatened with extinction from overexploitation. Therefore, it is important to find alternative approaches to meet the medical demand. This can be achieved using different strategies, including the assessment of the ability of the host microorganisms to biosynthesize pharmacologically active secondary metabolites differently, similarly, or identically to those produced by their host medicinal plant [13]. Therefore, a few endophytes from H. latiflora were isolated and investigated.

The first endophyte analyzed was MEXU 27095. Bioassay-guided fractionation of the active organic extract obtained from solid media culture led to the separation of three tridepsides, which were identified as thielavins A, J, and K (1 – 3) [14] ([Fig. 1]). All three compounds inhibited bakerʼs yeast α-glucosidase (αGHY) in a concentration-dependent manner with IC50 values of 23.8, 15.8, and 22.1 µM, respectively. Their inhibitory action was higher than that of acarbose (IC50 = 545 µM), used as a positive control. Kinetic analysis established that the three compounds acted as noncompetitive inhibitors with K i values of 27.8, 66.2 and 55.4 µM, respectively. Docking analysis predicted that 1 – 3 and acarbose bind to αGHY in a pocket close to the catalytic site for isomaltose. The α-glucosidase inhibitory properties of thielavin K (3) were corroborated in vivo since it induced noted antihyperglycemic action during an oral sucrose tolerance test (3.1, 10.0, and 31.6 mg/kg) in normal and nicotinamide-streptozotocin (NA-STZ) hyperglycemic mice. Thielavin K (3) also showed a hypoglycemic effect in vivo at the doses of 3.1 and 10 mg/kg when tested in normal and hyperglycemic mice. In both cases the effect was attained after 5 h and maintained throughout the experiment, and was comparable to that of glibenclamide [14]. Sakemi and coworkers previously demonstrated that compounds 1 – 3 were glucose-6-phosphatase inhibitors in vitro [15]. Altogether, these results revealed that thielavin-type tridepsides represent a new lead for the development of α-glucosidase inhibitors; specifically, compound 3 shows potential as an antidiabetic agent acting at different targets, namely, inhibiting the α-glucosidases at the intestinal levels or decreasing hepatic glucose output from glyconeogenesis and glycogenolysis. Unfortunately, compounds 1 – 3 showed poor solubility, which caused problems for further in vitro and in vivo assays.

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Fig. 1 Secondary metabolites isolated from endophyte MEXU 27095.

P. minimoides was also isolated as an endophyte from H. latiflora, although it has been previously obtained from different substrates including dung, Pinus tabulaeformis Carr., and Trametes hirsutum (Will. Fr.) S. F. Gray, a medicinal fungus collected from a dead hardwood branch in a dry forest in Hawaii [16]. A previous chemical investigation performed by other authors resulted in the isolation of a depsipeptide and two polyketides, sporminarins A and B [16], with antifungal properties against Aspergillus flavus Link [17]. In our exploration, extensive fractionation of an extract from the grain-based culture of P. minimoides led to the isolation of five new polyketides, two of them with novel skeletons, minimoidiones A (4) and B (5), corymbiferone C (6), corymbiferan lactone E (7), and 5-hydroxy-2,7-dimethoxy-8-methylnaphthoquinone (8), along with the known compounds preussochromone C (9), corymbiferone (10), brocaenol B (11), and ziganein (12) [18], [19] ([Fig. 2]). The structures of the new compounds 4 – 8 were elucidated using 1D and 2D NMR data analysis, along with density functional theory (DFT) calculations of NMR chemical shifts. The absolute configuration of 4 was established by a single-crystal X-ray diffraction analysis and time-dependent DFT electronic circular dichroism (TDDFT-ECD) calculations. Polyketides 4, 5, 9, and 10 significantly inhibited yeast α-glucosidase with IC50ʼs ranging from 2.9 to 155 µM. Among them, compound 5 showed the strongest effect (IC50 = 2.9 µM). In order to envisage the putative binding mode of compounds 4 and 5 with αGHY, docking analyses were carried out using the crystallized structure of αGHY. Minimoidione A (4) and the R and S enantiomers of 5 were docked into the validated α-glucosidase model. The results predicted that the R enantiomer of compound 5 binds in a site different from the catalytic domain. On the other hand, docking of compound 4 and the S stereoisomer of 5 suggested that they bind to the catalytic site of αGHY with higher affinities. Further work is in progress to test these polyketides in vivo.

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Fig. 2 Secondary metabolites isolated from endophyte P. minimoides.

The last endophyte from H. latiflora with α-glucosidase inhibitory activity was characterized as X. feejeensis. The genus Xylaria Hill ex Schrank comprises more than 300 species, some of which have received special attention due to their potential as sources of novel secondary metabolites. A recent review showed that more than 180 compounds, including sesquiterpenoids, diterpenoids, diterpene glycosides, triterpene glycosides, steroids, N-containing compounds, pyrone derivatives, and polyketides, have been isolated from this genus [20], [21]. Specifically, from X. feejeensis, integric acid, xylaropyrone, and the nonenolide xyolide have been isolated. During our investigations, we isolated two new compounds, pestalotin 4′-O-methyl-β-mannopyranoside (13) and 3S,4R-(+)-4-hydroxymellein (14), from an organic extract of a solid medium culture (rice). In addition, the known compounds 3S,4S-(+)-4-hydroxymellein (15), 3S-(+)-8-methoxymellein (16), coriloxine (17), and the quinone derivatives 18 and 19 were obtained [22] ([Fig. 3]). The absolute configuration of the stereogenic centers of 13 and 14 was determined using TDDFT-ECD calculations. Compounds 14 and 15 inhibited αGHY with IC50 values of 441 and 549 µM, respectively. Their activity was comparable to that of acarbose. Molecular docking predicted that both compounds bind to αGHY in a site different from the catalytic domain, which could imply an allosteric type of inhibition.

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Fig. 3 Secondary metabolites isolated from endophyte X. feejeensis.

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Coprophilous Penicillium spathulatum

P. spathulatum was collected aseptically from bat dung obtained in the Chontalcoatlán cave in the State of Guerrero. This fungus has a worldwide distribution and is found commonly in soil, air, water, ice, and food products, and is associated with different plants. HPLC analysis of the extrolites of some strains of P. spathulatum revealed that all of the isolates produced asperphenamate (20) and perinadine, some benzomalvins, breviones, cyclopenols, and related benzodiazepine alkaloids, and the least quinolactacins [23]. The defatted extract from P. spathulatum B35 grown in rice showed inhibitory activity against yeast α-glucosidase (IC50 = 56.5 µg/mL). Extensive chromatography of this active fraction led to the isolation of 20, the epimeric mixture (7 : 3) of quinolactacins A1 (21) and A2 (22), quinolactacin B as a racemate (23), quinolonimide (24), benzomalvin A (25), and 2-chloro-6-[2′(S)-hydroxypropyl]-1,3,8-trihydroxy-anthraquinone (26), a new chemical entity [24] ([Fig. 4]). Compound 20, the mixture of 21 and 22, racemate 23, and compound 25 inhibited yeast α-glucosidase in a concentration-dependent fashion with IC50 values of 8.3, 273.3, 57.3, and 383.2 µM, respectively. The α-glucosidase inhibitory properties of 25 were confirmed in vivo with an oral sucrose tolerance test in normal and hyperglycemic mice. Docking studies performed with conformers 25a and 25b indicated that they bind to yeast isomaltase (3A4A) in a different location than acarbose, whereas for human enzymes 3LPP, 2QMJ, and 3TOP, the binding occurred at the catalytic domain [24]. Compound 25 also showed antihyperalgesic activity in NA-STZ hyperglycemic mice, reducing formalin-induced hyperalgesic behavior during phase I at the dose of 31.6 µg/paw, and during phase II at 10 and 31.6 µg/paw. The benzodiazepine-GABAA receptor was ruled out as the molecular target of 25 on the basis of classical agonist-antagonist experiments.

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Fig. 4 Secondary metabolites isolated from coprophilous P. spathulatum.

The last fungus selected for the search of α-glucosidase inhibitors was M. flavorosea. From the active extract prepared from the grain-based culture, two new polyketides, namely, 8-chloroxylarinol A (27) and flavoroseoside (28), along with the known compounds xylarinol A (29), xylarinol B (30), massarigenins B and C (31 and 32), and clavatol (33), were isolated [25] ([Fig. 5]). The structures of 27, 28, and 32 were corroborated by single-crystal X-ray diffraction analysis. Compounds 29, 30, and 32 significantly inhibited αGHY. Oral administration of 32 significantly reduced the postprandial peak in a non-dose-dependent manner during an oral sucrose tolerance test using normal and NA-STZ-induced (50 – 130 mg/kg) hyperglycemic mice. In all cases, the effect was comparable to that of the positive control acarbose, thus revealing the antihyperglycemic potential of compound 32. Docking of 32 to hNt-MGAM and hCt-MGAM as well as to hNt-SI and y-IM predicted that it would bind to them far from the catalytic site; the interacting forces were mainly by hydrophobic contacts and hydrogen bonding (HB). The overall docking results were consistent with the in vitro α-glucosidase inhibitory properties of compound 32 and predicted that its inhibitory action could be exerted throughout an allosteric interaction with the enzymes [25]. Further research is in progress to assess how it is absorbed, distributed, metabolized, and excreted.

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Fig. 5 Secondary metabolites isolated from M. flavorosea.

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CaM Inhibitors

Calmodulin is the major ubiquitous Ca2+-binding protein of all eukaryotes involved in a variety of physiological and pathophysiological roles related to smooth muscle contraction/relaxation, cell motility, cytoskeleton architecture and function, cell proliferation, apoptosis, autophagy, metabolic homeostasis, ion channel function, phosphorylation/dephosphorylation of proteins, plant growth, reproductive processes, and gene expression, to mention a few. CaM controls these processes through the modulation of over 100 different proteins including enzymes such as calmodulin-dependent phosphodiesterase (PDE1), nitric oxide synthases (NOS), several kinases (NADK), ion channels, phosphatases, calcium-ATPase pumps, and ion channels [26].

Many natural products, including drugs, pesticides, and research tools, interact with CaM at different binding sites, provoking a series of conformational changes in the protein. This, in turn, modifies the activity of the enzymes regulated by this important protein. For the discovery of CaM inhibitors, several methods have been used, which were described in a recent review [26]. In our investigations, we have employed functional enzymatic assays with bovine brain CaM-sensitive cAMP phosphodiesterase (PDE1) and/or peas CaM-dependent nicotinamide adenine dinucleotide kinase (NADK) as reporter enzymes, SDS-PAGE, and/or fluorescent biological sensors (FBS) built with human CaM (hCaM) developed in recent years [27], [28], [29], [30], [31], [32], [33]. In some cases, in silico analyses were used to explore the potential binding site of the inhibitors. According to literature data, the Fungi Kingdom has yielded many important CaM inhibitors. Perhaps the ophiobolins isolated from several species of the genus Bipolaris has been the most thoroughly investigated [34]. In the course of our investigations, we have also discovered new CaM inhibitors from selected fungi from Mexico, which are summarized in the following sections.

Plant pathogen Phoma herbarum

The genus Phoma Saccardo consists of over 2000 species found all over the world. Numerous species of this genus are plant pathogens causing root infections and different spot/blotch diseases in several economically important crops [35]. Among the most relevant pathogens of an important variety of corn (Zea mays L.) in Mexico (Cacahuacintle corn) is P. herbarum. This species is distributed worldwide and found in a variety of substrates, including herbaceous and woody plants, soil, and water, and has also been reported as a pathogen of wild oats and dandelions [36], [37]. Chemical studies of organic extracts prepared from the culture media of P. herbarum TOX-01020 led to the isolation of three new nonenolides, namely, herbarumins I – III (34 – 36) ([Fig. 6]). The structure elucidation of the herbarumins was accomplished by chemical, spectroscopic, and computational methods [38], [39]. These compounds possess a unique 10-membered macrolide core, which, according to a recent review, has inspired many synthetic works all around the world [40].

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Fig. 6 Secondary metabolites isolated from plant pathogen P. herbarum.

The interaction of the nonenolides with CaM was assessed using an SDS-PAGE and the functional enzymatic assay with PDE1. In all cases, CaM treated with the lactones had lower electrophoretic mobility than untreated CaM, and the effect was comparable to that of chlorpromazine (CPZ), used as a positive control. The enzyme inhibition studies were consistent with these results. As in the case of ophiobolin A, the CaM inhibitor properties of herbarumins I – III (34 – 36) correlated well with a phytotoxic action because when tested against seedlings of Amaranthus hypochondriacus L. using the petri dish bioassay, a significant phytogrowth inhibitory activity was observed. This action was similar or higher than that of 2,2-dichlorophenoxyacetic acid (2,4-D) used as a positive control. Altogether, our results could be related with the observations of Schnick and Boland [41], who demonstrated that a combination of 2,4-D and P. herbarum produced enhanced control of dandelion. More recently, a few investigations on this fungus isolated from different substrates allowed for the isolation of several new bioactive compounds. Thus, a marine isolate of P. herbarum produced the polyketides arthropsadiol C and massarilactone H, which possessed moderate neuraminidase inhibitory activity [42]. From a P. herbarum endophyte of Aegle marmelos (L.) Correa, a few new antibacterial naphthalenes were isolated [43], whereas from P. herbarum PSU-H256 from Hevea brasiliensis (Willd. ex A. Juss.) Müll.Arg. some terezine, tyrosine, and hydantoin derivatives were characterized [44], [45].


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Coprophilous Guanomyces polythrix

G. polythrix was isolated from bat guano in the Cueva del Diablo (Devilʼs cave) in Tepozotlán, Morelos, Mexico. Since the morphological and molecular characteristics of this isolate were unique, the new genus Guanomyces M. C. González, Hanlin & Ulloa was proposed to put up the new species [46], [47]. Bioassay-guided fractionation of an organic extract from the fermentation broth and mycelium of G. polythrix led to the isolation of several compounds, including seven new naphthopyranone derivatives (37 – 43) and the known compounds rubrofusarin B (44), p-hydroxybenzoic acid (45) and its methyl ester (46), a xanthene carboxylic acid methyl ester (47), emodin (48), citrinin (49), and the ergostatetraen-3-one (50) [47], [48], [49] ([Fig. 7]). According to an SDS-PAGE, compounds 37 – 50 interacted with both spinach and bovine brain CaMs, but 37 – 44 and 50 inhibited the activity of PDE1 in a concentration-dependent manner. The inhibitory activity was higher or comparable to that of CPZ (IC50 = 10.6 µM), a well-known CaM inhibitor. Natural compounds 38 and 42 – 44 were also potent inhibitors of the complex spinach-CaM-NADK, with IC50 values of 22.0, 24.3, 13.3, and 17.1 µM, respectively. Phytotoxins 43 and 44 that possess a double bond between C-2 and C-3 were the most active CaM inhibitors. Once more, all compounds significantly inhibited the radicle growth of A. hypochondriacus and Echinochloa crus-galli (L.) P. Beauv. in a concentration-dependent manner, and were more potent than 2,4-D (IC50 = 1.8 × 10−4 and 8.8 × 10−4 M for A. hypochondriacus and E. crus-galli, respectively). Overall, the effect of the phytotoxins of G. polythrix with both enzyme complexes suggested that they may act as CaM antagonists in vivo, inhibiting the CaM-dependent phenomena during plant growth, although they could also interfere with other cellular metabolic processes [47], [48], [49].

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Fig. 7 Secondary metabolites isolated from coprophilous G. polythrix.

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Marine-derived Emericella sp. and Aspergillus stromatoides

As of now, less than 80 marine fungi have been taxonomically described from the Pacific Coast, Gulf of Mexico Coast, and Caribbean Coast, with just a small percentage of them subjected to chemical studies [50]. Among them, the marine fungus Emericella sp. MEXU 25379 and A. stromatoides were investigated as a source of new CaM inhibitors.

The genus Emericella Berk (Aspergillus anamorph) produces a variety of secondary metabolites with important biological properties like antitumor, antioxidant, antimicrobial, immunostimulant, and antiallergic, among others [51]. Emericella sp. MEXU 25379 was isolated from the surface of the soft coral Pacifigorgia rutilia collected at Marietas Islands in Nayarit, Mexico. Chemical analyses of an organic extract of the broth culture (Czapeck) afforded five new (51 – 55) and four known (56 – 59) prenylated xanthones ([Fig. 8]). Their structures were elucidated by spectroscopic, chemical (Mosher ester analysis), and molecular modeling methods. Their anti-CaM properties were assessed with the PDE1 assay, SDS-PAGE, and/or FBS [31], [51]. Compounds 52 and 57 (IC50 = 5.54 and 5.62 µM, respectively) inhibited the activation of PDE1 by CaM in a concentration-dependent manner and retarded the electrophoretic mobility of CaM. In both cases, the effects were comparable to those of CPZ. Furthermore, kinetic analyses revealed that 52 and 57 acted as competitive antagonists of CaM, interfering with the formation of the CaM-PDE1 active complex [51]. The affinity values of compounds 52 – 59 were measured using the fluorescent biosensor hCaM L39C-mBBr/V91C-mBBr (K d values between 3.7 and 498.4 nM) [52]. Finally, all compounds docked into CaM at site I, except for compounds 54 and 59, which bound to sites IV and III, respectively. These binding sites have been identified as the most common binding regions for most CaM ligands, and all the predicted binding affinities were in excellent agreement with the experimental values [31], [51].

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Fig. 8 Secondary metabolites isolated from marine-derived Emericella sp. MEXU 25379 and A. stromatoides.

The fungal strain A. stromatoides was isolated from the sandy soil of Sánchez Magallanes beach, State of Tabasco, Mexico [52]. Bioassay-guided fractionation of the organic extract from the mycelium and culture medium of A. stromatoides led to the isolation of a series of polyketides identified as emodin (48), ω-hydroxyemodin (60), citrinin (49), 47, and coniochaetone A (61) ([Fig. 8]). The latter was unambiguously established by X-ray analysis. The affinity of compounds 48 and 60 with hCaM was determined using the fluorescent biosensor hCaM M124C-mBBr (K d = 0.33 and 0.76 µM, respectively) and was slightly better than that of CPZ (K d = 1.25 µM). These results were in agreement with those of the theoretical inhibition constants obtained from docking analysis. The interactions observed in the docking results for 48 and 60 showed that they bind in the same hydrophobic pocket as CPZ and some antitumoral drugs. In turn, our finding might account for the cytotoxic effect of these well-known anthraquinones whose antitumoral properties have been the subject of a few patents [52].


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Fungal endophyte MEXU 26343

MEXU 26343 was isolated from selected adult and healthy leaves of H. latiflora and tested for its CaM inhibitor properties [53]. The endophytic fungus was cultured in moist rice, and its organic extract was subjected to chemical investigation, yielding the mixture E and Z of the known polyketide vermelhotin (62) and a new salicylic aldehyde derivative, namely, 9S,11R-(+)-ascosalitoxin (63) ([Fig. 9]). The mixture E and Z of 62 was not separable, but in the presence of TFA, the generation of a pyrylium trifluoroacetate was favored and explained the water solubility of 62. On the other hand, the structure and absolute configuration of the new compound 63 were established through extensive NMR spectroscopy and molecular modeling calculations at the DFT B3LYP/DGDZVP level, which included the comparison between theoretical and experimental optical rotation values. In addition, chemical transformations of 63 yielded suitable derivatives for NOESY and 1H-1H NMR coupling constant analyses, which reinforces the stereochemical assignment [53].

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Fig. 9 Secondary metabolites isolated from endophyte MEXU 26343.

The potential affinity of 62 and 63 with CaM was established using the fluorescent biosensor hCaM M124C-mBBr, but only compound 62 bound to the protein with a K d value similar to that of the classical CaM inhibitor CPZ (K d = 0.25 µM for 62, and 0.64 µM for CPZ). Docking analysis of the four possible conformers of 62 showed that all bound to CaM at site I, as did trifluoperazine, with affinities consistent with the results from the fluorescence quenching experiments using the hCaM M124C-mBBr biosensor [53]. These findings suggested that compound 62 might be useful as a tool for studying the role of CaM in several physiological and pathophysiological processes.


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Entomopathogen Isaria fumosorosea

The entomopathogen I. fumosorosea was isolated from the whitefly B. tabaci Gennadius. Because of its wide arthropod host range, this species has been used for the biological control of several economically important insect pests of agricultural crops [54]. The total extract of I. fumosorosea showed significant anti-CaM activity using the CaM biosensor hCaM M124C-AF 350. Beauverolides C (64), F (65), I (66), Ja (67), L (68), M (69), and N (70) were identified as the active constituents of the extract ([Fig. 10]). This group of lipophilic and neutral cyclotetradepsipeptides, containing linear and branched C9- or C11-β-hydroxy acid residues, has been previously reported in the genera Beauveria and Paecilomyces [55]. All isolated cyclotetradepsipeptides interacted with CaM with affinities ranging from 0.078 to 3.44 µM. The most active compound, beauverolide Ja (67), was almost tenfold more active than CPZ and contains a tryptophan moiety in its structure that could be related to its highest affinity. Docking analyses of compounds 64 – 70 into CaM revealed that, in all cases, they bind in the same pocket of CPZ and showed mainly hydrophobic interactions to the protein [55].

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Fig. 10 Secondary metabolites isolated from entomopathogen I. fumosorosea.

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Saprophyte Purpureocillium lilacinum

P. lilacinum was isolated from soil collected in a cave in Juxtlahuaca, State of Guerrero, Mexico, in 1998. This species is an emergent pathogen that causes severe human infections, but is also used as an important biological control agent against nematodes [56]. Bioassay-guided fractionation of an extract prepared from the culture medium and mycelium of P. lilacinum yielded two CaM inhibitors, namely, acremoxanthone C (71) and acremonidin A (72) ([Fig. 11]). Both compounds showed an important affinity (70-fold higher than CPZ) for CaM using the fluorescent biosensor hCaM M124C-mBBr. Interestingly, this level of affinity to CaM is unusual, since most CaM antagonists bind to the protein with much lower affinity, usually in the micromolar range [56]. Based on the observed extraordinary affinity to CaM, we completed the structural characterization of 71 using molecular modeling calculations, which included the comparison between theoretical and experimental specific rotation, 3 J C,H, and 3 J H,H values. Docking analysis predicted that compounds 71 and 72 bind to CaM at a similar site to KAR-2, which is unusual. This prediction was experimentally supported since 71 quenched the fluorescence of hCaM T110C-mBBr, a biosensor specially designed to target nonclassical inhibitors of CaM [56].

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Fig. 11 Secondary metabolites isolated from saprophyte P. lilacinum.

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Coprophilous Malbranchea aurantiaca

The genus Malbranchea Saccardo comprises around 30 species distributed worldwide and mainly isolated from decaying vegetation, soil, and animal dung (http://www.indexfungorum.org). M. aurantiaca was obtained from bat guano collected at the Juxtlahuaca cave located in Ramal del Infierno, State of Guerrero, Mexico. The mycelial and culture broth organic extract of this fungus yielded an eremophilane derivative (73), penicillic acid (74), and four rare indole alkaloids possessing an unusual bicyclo [2.2.2] diazaoctane ring system, namely, malbrancheamide (75) and malbrancheamide B (76), isomalbrancheamide B (77), and premalbrancheamide (78) [57], [58], [59] ([Fig. 12]).

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Fig. 12 Secondary metabolites isolated from coprophilous M. aurantiaca.

Compounds 75 – 78 have been fully characterized as CaM ligands by NMR, fluorescence, circular dichroism, computational, and enzymatic functional methods. Of the alkaloids with an hCaM M124C-mBBr biosensor, only 75 quenched significantly (K d = 1.1 µM). The monochlorinated derivatives (76 and 77) provoked only limited decreases in fluorescence quenching, and 78 provoked none. Thus, the presence of two chlorine atoms confers 75 to have the best affinity to hCaM. Docking analysis predicted that 75 binds in the hydrophobic pocket of CaM through HB and hydrophobic interactions with a few methionine (Met) residues of the protein. Indeed, NMR experiments confirmed these results, since in solution, 75 induced a diamagnetic shift of most of the Met-methyl resonances of the protein, in particular, to those of Met residues 36, 51, 71, 72, 76, 109, 124, 144, and 145 [27].

As for other CaM inhibitors, 75 – 77 induced significant vasorelaxant activity in an endothelium intact model in rat aorta rings, and a lesser effect in an endothelium denuded model. Compound 75 was the most active (EC50 = 2.7 µM) with a maximum effect of almost 100%, which is unusual for a natural product; the involvement of the nitric oxide-cGMP pathway was experimentally demonstrated. Furthermore, docking studies carried out with two crystallized eNOS domains, namely, oxygenase (PDB code 3NOS) and a CaM-binding peptide bound to CaM (PDB code 1NIW), predicted that the endothelium-independent relaxation exerted by 75 could be mediated by its CaM inhibitory properties throughout a positive modulation of eNOS. In addition, in a fluorescent-based experiment using the hCaM M124C-mBBr biosensor, it was demonstrated that 75 (K d = 0.55 µM) induced a perturbation of the Ca2+-hCaM-MLCK complex, which could also account for its vasorelaxant effect [60].


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Other Activities

Marine-facultative Aspergillus sp.

The marine-facultative Aspergillus sp. MEXU 27854 was isolated from sandy soil collected in the intertidal zone located in Caleta Bay, Acapulco, Guerrero, Mexico [61]. The intertidal regions are dynamic environments that support an immense biodiversity. In these ecosystems, fungi play important roles in the process of decomposition and mineralization of organic matter [62]. From the organic extract of a rice-based culture of Aspergillus sp. MEXU 27854, a series of dioxomorpholine derivatives (79 – 84) were isolated ([Fig. 13]). An extensive literature search revealed that the morpholine-2,5-dione ring system is rare in nature and mainly biosynthesized by fungi. Ergosecalinine, the first reported dioxomorpholine, was isolated in 1959 from Claviceps purpurea (Fr.) Tul. [63], the immunomodulator metacytofilin was obtained from the fungus Metarhizium sp. TA2759 [64], the compound lateritin, isolated from Gibberella lateritium W. C. Snyder & H. N. Hansen in 1993, was recently revised to beauvericin by extensive NMR and MS analyses [65], the cyclodidepsipeptides isolated as a mixture from the fungus Fusarium sporotrichioides Sherb., were identified by comparison with the synthetic series, and their stereostructure was studied by quantum chemical calculations [66], and, finally, PF1233 B was isolated from Aspergillus niveus Blochwitz in 2003 as a novel inhibitor of voltage-dependent sodium channels, and reported again as a new natural product with P-glycoprotein (Pgp) inhibitor properties in 2014 [67], [68], [69].

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Fig. 13 Secondary metabolites isolated from marine-facultative Aspergillus sp. MEXU 27854.

The structures of 79 – 84 were established by 1D and 2D NMR and HRESIMS data analysis, and the absolute configuration of 79 and 80 was elucidated by comparison of experimental and DFT calculated vibrational circular dichroism spectra. Finally, the cytotoxic properties of derivatives 81, 83, and 84 were determined using a panel of human cancer cell lines with different functional status for p53 and against a cell line (A549/doxorubicin) that overexpresses Pgp and presents developed resistance to doxorubicin [61].


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Agrochemicals

Like pharmaceuticals, many pesticides are based on fungal natural products; these could belong to the category of biopesticides or biochemical pesticides. These agents have become attractive in recent years because the novelty of their structures offers the possibility of finding compounds with new modes of action, thus diminishing the induction of resistance [70]. Among the most relevant pesticides developed from fungal natural products are the strobilurins derivatives. The natural strobilurins were originally found in several fungi, including Strobilurus tenacellus (Pers.) Singer, Xerula spp., and Cyphellopsis anomala (Pers.) Donk. These types of compounds inhibit the electron transfer in mitochondrial respiration by binding to the ubiquinol site of cytochrome b. In the case of biopesticides, a few formulations with Colletotrichum gloeosporioides f.sp. (Penz.) Penz. & Sacc. (BioMal and Collego), Phoma macrostoma Montagne (Ecosense), which has been developed and applied successfully for weed control, and Myrothecium verrucaria (Alb. & Schwein.) Ditmar (DiTera) have been made against plant parasitic nematodes. Recently, a few reviews have been published emphasizing the urgent need for new pesticides with safer toxicological and environmental profiles and new modes of action [70], [71]. With these considerations, we have investigated several fungi from Mexico in order to discover new leads for the development of biochemical pesticides, in particular, for weed control affecting different molecular targets.


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Endophytes from Plants Collected in El Eden Ecological Reserve, Quintana Roo, Mexico

El Eden Ecological Reserve is a natural protected area situated in the State of Quintana Roo, Mexico, and is part of the Mesoamerican tropical rain forest. Nowadays, many multidisciplinary research projects take place in the region, with fungal biodiversity monitoring and bioprospection projects being two of them [72]. In this context, E. gomezpompae was isolated from surface sterilized leaves of the medicinal plant C. acuminata [73]. A chemical investigation of the mycelium of E. gomezpompae resulted in the isolation of eight naphthoquinone-spiroketals, namely, preussomerins EG1 – EG4 (85 – 88), palmarumycins EG1 (89), CP2 (90), CP17 (91), and CP19 (92) as well as 50 [74], [75] ([Fig. 14]).

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Fig. 14 Secondary metabolites isolated from endophyte E. gomezpompae.

Compounds 85 – 87 and the acetyl derivatives 85a and 85b showed significant antifungal and anti-oomycete activities against four economically important phytopathogens, Phythophtora capsici Leonian, Phythophtora parasitica Dastur, Fusarium oxysporum Schltdl., and Alternaria solani (Cooke) Wint. Their IC50 values ranged between 47.8 and 313.0 µg/mL. Preussomerin EG1 (85) caused complete growth inhibition of P. parasitica, F. oxysporum, and P. capsici. In the case of P. capsici, 85 (IC50 = 5.61 × 10−5 M) was more active than the commercial fungicide Captan (IC50 = 1.53 × 10−4 M). A. solani was only affected by 86 and 87. Compounds 85 – 88 inhibited the germination of A. hypochondriacus, Solanum lycopersicum L., and E. crus-galli, being more potent than the positive control Rival. Compound 86 significantly inhibited (> 50%) root elongation of the three species tested, but 87 and 92 affected (> 50%) both A. hypochondriacus and E. crus-galli. Compound 86 inhibited respiration of all seedlings tested, but 88 and 89 of S. lycopersicum and E. crus-galli. Furthermore, oxygen consumption in intact mitochondria was significantly inhibited by compounds 86 – 88 and 90 – 93, but the effect was lower than that of 2,4-dinitrophenol [74]. The study of compounds 85, 88, 90, and 91 in a series of photosynthesis light reactions in freshly lysed spinach thylakoids (ATP synthesis, electron transport rate basal, phosphorylating, uncoupled and partial reactions of the photosystems I and II, and chlorophyll a fluorescence of the photosystem II) revealed that they are Hillʼs reaction inhibitors [76]. They also interacted at the acceptor site of the photosystem II in a similar way as the commercial herbicide Diuron, as demonstrated by chlorophyll a fluorescence experiments. Consequently, these compounds could be considered promising leads for developing new herbicides for utilization in modern agriculture.

Muscodor yucatanenis MEXU 25511 [77], a new fungal species, and A. camptosporum MEXU 26354 [78] were isolated from the leaves of B. simaruba, which is a frequent codominant medicinal tree of the Yucatan Peninsula; the Mayan communities use this plant as an analgesic, antimycotic, and anti-inflammatory agent. So far, all Muscodor species are endophytes that produce mixtures of volatile organic compounds (VOCs). These mixtures are useful as pesticides in living environments since they are readily converted to a gaseous phase at room temperature due to their low vapor pressure [79]. The composition and relative abundance of VOCs produced by microorganisms can be established using headspace solid-phase microextraction.

The VOCs of M. yucatanensis were lethal to the endophytes Colletotrichum sp., Phomopsis sp., and Guignardia mangiferae, A. J. Roy, and to the phytopathogens P. capsici, P. parasitica, Rhizoctonia sp., and A. solani. Root elongation of A. hypochondriacus, S. lycopersicum, and E. crus-galli was also inhibited by the volatile mixture. M. yucatanensis’ VOCs included 38 compounds that were identified by GC-MS, mainly, alcohols, acids, esters, ketones, naphthalene derivatives, benzene derivatives, terpenoids, and aliphatic hydrocarbons. The organic extracts from the culture medium and mycelium of M. yucatanensis were also active against the same endophytes, phytopathogens, and plants tested. In the case of A. hypochondriacus, the culture medium extract (IC50 = 194.3 µg/mL) was more active than the commercial herbicide Rival (IC50 = 234.42 µg/mL). According to GC-MS, the extracts and VOCs shared 12 compounds, including benzene derivatives, phenolic compounds, cyclopentadienes, esters, lactones, alkanes, aldehydes, and carboxylic acids [80]. Recently, Qadri and coworkers [81] isolated a new strain of this fungus (Ni30) from a leaf of Elleanthus sp. at the Reserva Natural Punta Gorda, Nicaragua. The chemical composition of the volatile mixture of Ni30 was similar to those described by Macías-Rubalcava and coworkers [80]. The Ni30 strain also biosynthesized the macrolactone brefeldin A.

The genus Acremonium Link contains more than 200 species, which could be saprophytic, pathogenic, or endophytic. This genus is known for producing many interesting bioactive secondary metabolites, like the β-lactam antibiotics cephalosporins, the tremorgenic indole-diterpene alkaloids lolitrems, sesquiterpenoids, diterpenoids and triterpenoids with different skeletons, ophiobiolin D, a few meroterpenoids, a variety of polyketides, and peptides [81]. Bioassay-guided fractionation of the mycelial extract from A. camptosporum MEXU 26354 led to the isolation of six heterodimeric polyketides, acremoxanthone E (93), acremoxanthone A – C (94, 95, and 71), and acremonidins A (72) and B (96) [82] ([Fig. 15]). All compounds showed anti-oomycete activity against Pythium aphanidermatum Edson, Phytophthora cinnamomi Rands, P. capsici, and P. parasitica, reducing the diameter growth of most target oomycetes in a concentration-dependent manner, with IC50 values ranging between 6 – 38 µM, and the activity was comparable to the commercial fungicide Ridomil Gold 4E. However, in the case of P. cinnamomi, polyketides 93, 94, and 71 were more active than the commercial fungicide. Unusually, this fungus biosynthesizes three different types of heterodimeric polyketides linked by a bicyclo[3.2.2]nonene: xanthoquinodins, acremonidins, and acremoxanthones.

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Fig. 15 Secondary metabolites isolated from endophyte A. camptosporum MEXU 26354.

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Endophytes from Plants Collected in Sierra de Huautla Biosphere Reserve

Xylaria feejeensis SM3e-1b

The Sierra de Huautla Biosphere Reserve (REBIOSH), recognized by the MAB-UNESCO program and included in the world net of biosphere reserves, is located in Quilamula at Tlalquitenango, Morelos, Mexico. This area represents the largest natural protected area devoted to the conservation of a tropical dry forest in Central Mexico, and is an important reservoir of endemic species, including fungal endophytes (www.conanp.gob.mx).

From symptomless healthy leaves of the tree S. macrocarpum, the strain X. feejeensis SM3e-1b was isolated [83]. Bioassay-guided fractionation of the extracts from the culture medium and mycelium led to the isolation of coriloxine (17) and two quinone derivatives, 18 and fumiquinone B (97). In addition, four semisynthetic compounds from 17 were prepared (17a – 17d) ([Fig. 16]). All compounds showed a phytotoxic effect in a concentration-dependent manner on germination, elongation of the root, and oxygen uptake (respiration) of seedlings from Trifolium pratense L., Medicago sativa L., A. hypochondriacus, and Panicum miliaceum L. In general, the IC50 values for all these activities ranged between 0.1 – 1.1 mM, which were comparable to the values obtained for the commercial herbicides Rival and ExterPro [83]. Of all the compounds, only 17a and 17d inhibited ATP synthesis, basal and uncoupled electron transport, and enhanced the phosphorylating electron transport and Mg2+-ATPase enzymatic activity when tested in a series of photosynthetic light reactions in freshly lysed spinach chloroplasts. Overall, these results indicated that 17a acted as an uncoupler and a weak Hillʼs reaction inhibitor, whereas 17d acted as a Hillʼs reaction inhibitor at the photosystem II [84]. Thus, coriloxine derivatives represented new leads for the development of novel herbicides.

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Fig. 16 Secondary metabolites isolated from endophyte X. feejeensis SM3e-1b.

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Xylaria sp. PB3f3

The endophyte Xylaria sp. PB3f3 was isolated from leaves of H. brasiletto collected at the REBIOSH. Based on phylogenetic studies, the genera Muscodor and Xylaria are anamorphs. In a multiple antagonism bioassay during 40 days, the VOCs produced by Xylaria sp. PB3f3 significantly inhibited the radial growth of two oomycetes, P. aphanidermatum (78.3%) and P. capsici (48.3%), and two fungi, A. solani (24.5%), and F. oxysporum (24.2%) [85]. Furthermore, Xylaria sp. PB3f3, in simple direct antagonism bioassays, produced a significant inhibitory effect at distance of 90% over the growing of the four plant pathogens. On the other hand, the VOCs from 30- and 20-day cultures significantly inhibited the root growth of A. hypochondriacus (27.6%) and S. lycopersicum (53.2%), respectively. From the mixtures obtained at days 10 and 30 of culturing, 2-methyl-1-butanol and 2-methyl-1-propanol were identified as the most abundant components. Both compounds strongly inhibited root growth and respiration in the seedlings of A. hypochondriacus and S. lycopersicum, with IC50 values ranging between 4.6 – 48.2 µg/mL and 23.2 – 130.0 µM, respectively [85].


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Nodulisporium and Hypoxylon

The genus Hypoxylon and its anamorph Nodulisporium are well-known producers of antimicrobial VOCs [86]. From healthy leaves of G. sepium collected in the REBIOSH, the endophyte Nodulisporium sp. GS4d2II1a was isolated. VOCs and diffusible metabolites of Nodulisporium sp. showed anti-oomycete (P. aphanidermatum, P. capsici, Phythophtora palmivora, P. cinnamomi, P. parasitica, Pythium ultimum, and Pythium polytylum) and antifungal (A. solani and F. oxysporum) activities when evaluated using three types of antagonism bioassays, and monitored at different ages of the fungus (3 to 6 days of growth culture) and interaction conditions. The growth of the oomycetes and fungi was inhibited in all cases, and, as visually observed in the petri dish, their mycelia were partially or completely replaced. In addition, VOCs inhibited the growth of three oomycetes (P. parasitica, 29.7%; P. cinnamomi, 18.1%; and P. capsici, 25.7%) and one fungus (F. oxysporum, 21.6%) after 3 days of antagonism using divided plates. VOCs were not active after 5 and 7 days of the fungal culture. Finally, the VOCs resulting from Nodulisporium sp. grown for 3 and 5 days in PDA at 28 °C, and from the interaction of Nodulisporium sp. with P. aphanidermatum and Nodulisporium sp. with Nodulisporium sp., were analyzed by GC-MS (70 VOCs detected). The results revealed four different volatile profiles, however, the main metabolites were terpenes, which represent over 60% of the total, with eucalyptol, limonene, and ocimene being among the most predominant. The remaining compounds were benzene derivatives, esters, ketones, alcohols, and carboxylic acids, including 2-methyl-1-butanol, and 3-methyl-1-butanol as the most relevant [86].


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Hypoxylon anthochroum

The endophyte H. anthochroum Blaci was isolated from leaves of Bursera lancifolia collected at REBIOSH [87]. The VOCs produced by this endophyte exhibited a significant phytotoxic effect on seed germination, root elongation, and seedling respiration of A. hypochondriacus, P. miliaceum, T. pratense, and M. sativa, the majority with inhibition values over 40%. Furthermore, the VOCs slightly affected the growth of the plant pathogenic fungi A. solani and F. oxysporum, and the oomycetes P. ultimum and P. capsici. Once more, eucalyptol was the most predominant compound in the VOCs analyzed. On the other hand, the culture medium and mycelium extracts of H. anthochroum showed a high phytotoxic activity on the four test plants. From these, phenylethyl alcohol, 2-methyl-1-butanol, eucalyptol, and terpinolene were the most predominant metabolites. Pure phenylethyl alcohol and eucalyptol were also evaluated in the same vegetal processes, displaying IC50 values between 21.4 µg/mL and > 500.0 µg/mL, and 11.6 µg/mL and > 500.0 µg/mL, respectively. The IC50 values of the positive control Rival were found between 14.8 µg/mL and > 500.0 µg/mL [87].

Recently, six pure compounds (phenylethyl alcohol, 2-methyl-1-butanol, 3-methyl-1-butanol, eucalyptol, ocimene, and terpinolene) present in the VOCs of Nodulisporium sp. GS4d2II1 and H. anthochroum were evaluated in vivo and in vitro against F. oxysporum [88]. In vivo studies were performed inoculating the pathogen into cherry tomatoes. All compounds, and particularly the mixture of the six, significantly inhibited the growth of the mycelium on the wounds of infected tomatoes in a concentration-dependent manner. The in vitro assay, using agar dilution and gas phase methods, revealed that the VOCs mixture significantly affected the respiration and cell membrane permeability of the target fungus. The damage rate caused by individual compounds and the VOCsʼ mixtures on the cell membrane of F. oxysporum was evaluated through the measurement of electrolytes leak (% relative conductivity). After 8 h of treatment, the best effect was observed with 2-methyl-1-butanol (45.4%), phenylethyl alcohol (43.1%), and the VOCsʼ mixture (42.9%). According to a microscopic analysis of mycelia fresh preparations, the pure compounds and the six compoundsʼ mixture at 1000 µg/mL induced important ultrastructure morphological changes in F. oxysporum hyphae. Ocimene and the mixture induced a vacuolization process and thickening and thinning on the middle and the tips, respectively. Finally, an inhibitory effect on the respiration were observed with all treatments, which could be attributed to the proliferation of vacuoles and the severe vacuolization process provoked by the rupture of hyphae [88]. VOCsʼ mixture showed the greatest oxygen consumption inhibition (97.1%) after 8 h incubation (IC50 = 183.9 µg/mL). These results revealed that VOCs are promising candidates for the development of biopesticides, having great potential for tomatoes postharvest treatment against diseases caused by F. oxysporum.


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Coprophilous Penicillium sp. G1-a14

Penicillium sp. G1-a14 was also isolated from bat dung obtained in the Chontalcoatlán cave in the State of Guerrero [89]. This fungus was selected for bioassay-directed fractionation on the basis of its phytogrowth inhibitory activity against seedlings of A. hypochondriacus and E. crus-galli (IC50 = 46.2 and 184.7 µg/mL, respectively). Extensive chromatography of the active extract led to the isolation of a new eremophilane sesquiterpene (98), along with three known analogues, namely, isopetasol (99), sporogen AO-1 (100), and dihydrosporogen AO-1 (101) ([Fig. 17]). Only compounds 100 and 101 revealed a concentration-dependent inhibition on radicle elongation against A. hypochondriacus (IC50 = 0.17 mM for both compounds) and E. crus-galli (IC50 = 0.17 and 0.30 mM, respectively) with IC50 values similar to tricolorin A, used as a positive control [89]. The eremophilane-type sesquiterpenoid is common in Penicillium, Aspergillus, and Xylaria species, and a few of them have also shown important phytotoxic activity.

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Fig. 17 Secondary metabolites isolated from coprophilous Penicillium sp. G1-a14.

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Concluding Remarks and Outlook

In the last 20 years, more than 100 secondary metabolites from various classes have been identified from fungi from different substrates throughout Mexico. Some of these natural products possessed new scaffolds and have attracted the attention of synthetic chemists, such as in the case of herbarumins I – III (34 – 36) and malbrancheamides (75 – 78). Most of these fungal compounds displayed diverse bioactivities of medicinal and/or agrochemical interest. Thus, a few showed potential as antidiabetic drugs with α-glucosidase inhibitory activity. Preclinical pharmacological evidence indicated that most of them were more active than acarbose, and some, like benzomalvin A (25), also possess antihyperalgesic properties of utility for treating diabetic neuropathies. Another, malbrancheamide (75), is a vasorelaxant compound with a maximum effect of almost 100%, which is unusual for a natural product. The effect is mediated by CaM inhibitory properties throughout a positive modulation of eNOS and a perturbation of the Ca2+-hCaM-MLCK complex. A series of dioxomorpholine derivatives (81, 83, and 84) were cytotoxic in a panel of human cancer cell lines, with a different functional status for p53, and against a cell line (A549/doxorubicin) that overexpressed Pgp and developed resistance to doxorubicin. A few were CaM inhibitors, valuable for the study of CaM-mediated physiological processes or pharmacological properties in mammals and plants. Among the isolates, the prenylated xanthones 52 and 57 and acremoxanthone C (71) were the best CaM inhibitors. In the agrochemical area, many active antifungal, anti-oomycetes, and phytotoxic agents more active than commercial products were discovered. The VOCs of several species, including those from the new species M. yucatanensis, showed promise as pest control agents. In some cases, their mode of action was also established. A few new fungal species were discovered, and a new genus, Guanomyces, was created to accommodate G. polythrix. The fact that Mexican fungi are still understudied shows that many more new scaffolds and several drug and agrochemical leads are likely to be discovered in the future. Thus, bioprospecting for structurally unique and bioactive metabolites from Mexican fungi has great potential for the discovery of new drug candidates in various applications in clinics and the agrochemical area.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

The work summarized in this paper was supported by grants from CONACyT (81017, 179194, 219765, and 236564) and DGAPA-UNAM (IA205017, IN207117, and IN217516). We are indebted to all graduate students, postdoctoral fellows, and collaborators whose names appear in the work cited for their important contributions to this work. We also thank Dirección General de Cómputo y de Tecnologías de Información y Comunicación (DGTIC), UNAM, for providing the resources to carry out computational calculations through the Miztli system.

* Part of this special issue is dedicated to Women in Natural Products Science.


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  • 18 Leyte-Lugo M, Figueroa M, González MC, Glenn AE, González-Andrade M, Mata R. Metabolites from the endophytic fungus Sporormiella minimoides isolated from Hintonia latiflora . Phytochemistry 2013; 96: 273-278
  • 19 Rangel-Grimaldo M, Rivero-Cruz I, Madariaga-Mazón A, Figueroa M, Mata R. alpha-Glucosidase inhibitors from Preussia minimoides double dagger. J Nat Prod 2017; 80: 582-587
  • 20 Song F, Wu SH, Zhai YZ, Xuan QC, Wang T. Secondary metabolites from the genus Xylaria and their bioactivities. Chem Biodivers 2014; 11: 673-694
  • 21 Macías-Rubalcava ML, Sánchez-Fernández RE. Secondary metabolites of endophytic Xylaria species with potential applications in medicine and agriculture. World J Microbiol Biotechnol 2016; 33: 15
  • 22 Rivera-Chávez J, Figueroa M, González MC, Glenn AE, Mata R. alpha-Glucosidase inhibitors from a Xylaria feejeensis associated with Hintonia latiflora . J Nat Prod 2015; 78: 730-735
  • 23 Frisvad JC, Houbraken J, Popma S, Samson RA. Two new Penicillium species Penicillium buchwaldii and Penicillium spathulatum, producing the anticancer compound asperphenamate. FEMS Microbiol Lett 2013; 339: 77-92
  • 24 Del Valle P, Martínez AL, Figueroa M, Raja HA, Mata R. Alkaloids from the fungus Penicillium spathulatum as alpha-glucosidase inhibitors. Planta Med 2016; 82: 1286-1294
  • 25 Verastegui-Omana B, Rebollar-Ramos D, Pérez-Vásquez A, Martínez AL, Madariaga-Mazón A, Flores-Bocanegra L, Mata R. alpha-Glucosidase inhibitors from Malbranchea flavorosea . J Nat Prod 2017; 80: 190-195
  • 26 Mata R, Figueroa M, González-Andrade M, Rivera-Chávez JA, Madariaga-Mazón A, Del Valle P. Calmodulin inhibitors from natural sources: an update. J Nat Prod 2015; 78: 576-586
  • 27 Figueroa M, González-Andrade M, Sosa-Peinado A, Madariaga-Mazón A, Del Río-Portilla F, González Mdel C, Mata R. Fluorescence, circular dichroism, NMR, and docking studies of the interaction of the alkaloid malbrancheamide with calmodulin. J Enzyme Inhib Med Chem 2011; 26: 378-385
  • 28 González-Andrade M, Benito-Pena E, Mata R, Moreno-Bondi MC. Biosensor for on-line fluorescent detection of trifluoroperazine based on genetically modified calmodulin. Anal Bioanal Chem 2012; 402: 3211-3218
  • 29 González-Andrade M, Figueroa M, Rodríguez-Sotres R, Mata R, Sosa-Peinado A. An alternative assay to discover potential calmodulin inhibitors using a human fluorophore-labeled CaM protein. Anal Biochem 2009; 387: 64-70
  • 30 González-Andrade M, Mata R, Madariaga-Mazón A, Rodríguez-Sotres R, Del Pozo-Yauner L, Sosa-Peinado A. Importance of the interaction protein-protein of the CaM-PDE1A and CaM-MLCK complexes in the development of new anti-CaM drugs. J Mol Recognit 2013; 26: 165-174
  • 31 Gonzalez-Andrade M, Rivera-Chavez J, Sosa-Peinado A, Figueroa M, Rodriguez-Sotres R, Mata R. Development of the fluorescent biosensor hCalmodulin (hCaM)L39C-monobromobimane(mBBr)/V91C-mBBr, a novel tool for discovering new calmodulin inhibitors and detecting calcium. J Med Chem 2011; 54: 3875-3884
  • 32 González-Andrade M, Rodríguez-Sotres R, Madariaga-Mazón A, Rivera-Chávez J, Mata R, Sosa-Peinado A, Del Pozo-Yauner L, Arias-Olguín II. Insights into molecular interactions between CaM and its inhibitors from molecular dynamics simulations and experimental data. J Biomol Struct Dyn 2016; 34: 78-91
  • 33 Velázquez-López I, León-Cruz E, Pardo JP, Sosa-Peinado A, González-Andrade M. Development of new hCaM-Alexa Fluor® biosensors for a wide range of ligands. Anal Biochem 2017; 516: 13-22
  • 34 Kong Au T, Chow Leung P. Identification of the binding and inhibition sites in the calmodulin molecule for ophiobolin A by site-directed mutagenesis. Plant Physiol 1998; 118: 965-973
  • 35 Rai MK, Tiwari VV, Irinyi L, Kövics GJ. Advances in taxonomy of genus Phoma: polyphyletic nature and role of phenotypic traits and molecular systematics. Indian J Microbiol 2014; 54: 123-128
  • 36 Domsch KH, Gams W, Anderson TH. Compendium of soil Fungi, Vol. 1. London: Academic Press (London) Ltd.; 1980
  • 37 Neumann Brebaum S, Boland GJ. First report of Phoma herbarum and Phoma exigua as pathogens of dandelion in southern Ontario. Plant Dis 1999; 83: 200
  • 38 Rivero-Cruz JF, García-Aguirre G, Cerda-García-Rojas CM, Mata R. Conformational behavior and absolute stereostructure of two phytotoxic nonenolides from the fungus Phoma herbarum . Tetrahedron 2000; 56: 5337-5344
  • 39 Rivero-Cruz JF, Macias M, Cerda-García-Rojas CM, Mata R. A new phytotoxic nonenolide from Phoma herbarum . J Nat Prod 2003; 66: 511-514
  • 40 Martínez-Luis S, Pérez-Vásquez A, Mata R. Natural products with calmodulin inhibitor properties. Phytochemistry 2007; 68: 1882-1903
  • 41 Schnick PJ, Boland GJ. 2,4-D and Phoma herbarum to control dandelion (Taraxacum officinale). Weed Sci 2017; 52: 808-814
  • 42 Zhang GF, Han WB, Cui JT, Ng SW, Guo ZK, Tan RX, Ge HM. Neuraminidase inhibitory polyketides from the marine-derived fungus Phoma herbarum . Planta Med 2012; 78: 76-78
  • 43 Gond SK, Mishra A, Sharma VK, Verma SK, Kharwar RN. Isolation and characterization of antibacterial naphthalene derivative from Phoma herbarum, an endophytic fungus of Aegle marmelos . Curr Sci 2013; 105: 167-169
  • 44 Maha A, Rukachaisirikul V, Phongpaichit S, Preedanon S, Sakayaroj J. Tyrosine and hydantoin derivatives from the fungus Phoma herbarum PSU-H256 isolated from Hevea brasiliensis . Tetrahedron 2017; 73: 4597-4601
  • 45 Maha A, Rukachaisirikul V, Saithong S, Phongpaichit S, Poonsuwan W, Sakayaroj J, Saparpakorn P, Hannongbua S. Terezine derivatives from the fungus Phoma herbarum PSU-H256. Phytochemistry 2016; 122: 223-229
  • 46 González MC, Hanlin RT, Ulloa M. Guanomyces, a new genus of Ascomycetes from Mexico. Mycologia 2000; 92: 1138-1148
  • 47 Macías M, Ulloa M, Gamboa A, Mata R. Phytotoxic compounds from the new coprophilous fungus Guanomyces polythrix . J Nat Prod 2000; 63: 757-761
  • 48 Macías M, Gamboa A, Ulloa M, Toscano RA, Mata R. Phytotoxic naphthopyranone derivatives from the coprophilous fungus Guanomyces polythrix . Phytochemistry 2001; 58: 751-758
  • 49 Mata R, Gamboa A, Macías M, Santillán S, Ulloa M, González MC. Effect of selected phytotoxins from Guanomyces polythrix on the calmodulin-dependent activity of the enzymes cAMP phosphodiesterase and NAD-kinase. J Agric Food Chem 2003; 51: 4559-4562
  • 50 González MC, Hanlin RT, Ulloa M. A checklist of higher marine fungi of Mexico. Mycotaxon 2001; 80: 241-253
  • 51 Figueroa M, González Mdel C, Rodríguez-Sotres R, Sosa-Peinado A, González-Andrade M, Cerda-García-Rojas CM, Mata R. Calmodulin inhibitors from the fungus Emericella sp. Bioorg Med Chem 2009; 17: 2167-2174
  • 52 González-Andrade M, Del Valle P, Macías-Rubalcava ML, Sosa-Peinado A, González MC, Mata R. Calmodulin inhibitors from Aspergillus stromatoides . Chem Biodivers 2013; 10: 328-337
  • 53 Leyte-Lugo M, González-Andrade M, González MC, Glenn AE, Cerda-García-Rojas CM, Mata R. (+)-Ascosalitoxin and vermelhotin, a calmodulin inhibitor, from an endophytic fungus isolated from Hintonia latiflora . J Nat Prod 2012; 75: 1571-1577
  • 54 Kim JS, Je YH, Roh JY. Production of thermotolerant entomopathogenic Isaria fumosorosea SFP-198 conidia in corn-corn oil mixture. J Ind Microbiol Biotechnol 2010; 37: 419-423
  • 55 Madariaga-Mazón A, González-Andrade M, Toriello C, Navarro-Barranco H, Mata R. Potent anti-calmodulin activity of cyclotetradepsipeptides isolated from Isaria fumosorosea using a newly designed biosensor. Nat Prod Commun 2015; 10: 113-116
  • 56 Madariaga-Mazón A, González-Andrade M, Gonzalez MC, Glenn AE, Cerda-García-Rojas CM, Mata R. Absolute configuration of acremoxanthone C, a potent calmodulin inhibitor from Purpureocillium lilacinum . J Nat Prod 2013; 76: 1454-1460
  • 57 Martínez-Luis S, González MC, Ulloa M, Mata R. Phytotoxins from the fungus Malbranchea aurantiaca . Phytochemistry 2005; 66: 1012-1016
  • 58 Martínez-Luis S, Rodríguez R, Acevedo L, González MC, Lira-Rocha A, Mata R. Malbrancheamide, a new calmodulin inhibitor from the fungus Malbranchea aurantiaca . Tetrahedron 2006; 62: 1817-1822
  • 59 Figueroa M, González MC, Mata R. Malbrancheamide B, a novel compound from the fungus Malbranchea aurantiaca . Nat Prod Res 2008; 22: 709-714
  • 60 Madariaga-Mazón A, Hernández-Abreu O, Estrada-Soto S, Mata R. Insights on the vasorelaxant mode of action of malbrancheamide. J Pharm Pharmacol 2015; 67: 551-558
  • 61 Aparicio-Cuevas MA, Rivero-Cruz I, Sánchez-Castellanos M, Menéndez D, Raja HA, Joseph-Nathan P, González MDC, Figueroa M. Dioxomorpholines and derivatives from a marine-facultative Aspergillus species. J Nat Prod 2017; 80: 2311-2318
  • 62 Li W, Wang M, Bian X, Guo J, Cai L. A high-level fungal diversity in the intertidal sediment of Chinese seas presents the spatial variation of community composition. Front Microbiol 2016; 7: 2098
  • 63 Abe M, Yamano T, Yamatodani S, Kōzu Y, Kusumoto M, Komatsu H, Yamada S. On the new peptide-type ergot alkaloids, ergosecaline and ergosecalinine. Bull Chem Soc Jpn 1959; 23: 246-248
  • 64 Iijima M, Masuda T, Nakamura H, Naganawa H, Kurasawa S, Okami Y, Ishizuka M, Takeuchi T, Iitake Y. Metacytofilin, a novel immunomodulator produced by Metarhizium sp. TA2759. J Antibiot (Tokyo) 1992; 45: 1553-1556
  • 65 Ola ARB, Aly AH, Lin W, Wray V, Debbab A. Structural revision and absolute configuration of lateritin. Tetrahedron Lett 2014; 55: 6184-6187
  • 66 Smelcerovic A, Yancheva D, Cherneva E, Petronijevic Z, Lamshoeft M, Herebian D. Identification and synthesis of three cyclodidepsipeptides as potential precursors of enniatin B in Fusarium sporotrichioides . J Mol Struct 2011; 985: 397-402
  • 67 Khalil ZG, Huang XC, Raju R, Piggott AM, Capon RJ. Shornephine A: structure, chemical stability, and P-glycoprotein inhibitory properties of a rare diketomorpholine from an Australian marine-derived Aspergillus sp. J Org Chem 2014; 79: 8700-8705
  • 68 Kushida N, Yaguchi T, Miike N. New active substance PF1233A substance and PF1233B substance, and their methods for producing the same and pharmaceutical composition using the same. JP 2003096080; 2003.
  • 69 Nakadate S, Nozawa K, Horie H, Fujii Y, Nagai M, Komai SI, Hosoe T, Kawai KI, Yaguchi T, Fukushima K. New dioxomorpholine derivatives, javanicunine A and B, from Eupenicillium javanicum . Heterocycles 2006; 68: 1969-1972
  • 70 Dayan FE, Duke SO. Natural compounds as next-generation herbicides. Plant Physiol 2014; 166: 1090-1105
  • 71 Cantrell CL, Dayan FE, Duke SO. Natural products as sources for new pesticides. J Nat Prod 2012; 75: 1231-1242
  • 72 Anaya AL, Mata R, Sims JJ, González-Coloma A, Cruz-Ortega R, Guadano A, Hernández-Bautista BE, Midland SL, Ríos R, Gómez-Pompa A. Allelochemical potential of Callicarpa acuminata . J Chem Ecol 2003; 29: 2761-2776
  • 73 González MC, Anaya AL, Glenn AE, Saucedo-García A, Macías-Rubalcava ML, Hanlin RT. A new endophytic ascomycete from El Eden Ecological Reserve, Quintana Roo, Mexico. Mycotaxon 2007; 101: 251-260
  • 74 Macías-Rubalcava ML, Ruiz-Velasco Sobrino ME, Meléndez-González C, Hernández-Ortega S. Naphthoquinone spiroketals and organic extracts from the endophytic fungus Edenia gomezpompae as potential herbicides. J Agric Food Chem 2014; 62: 3553-3562
  • 75 Macías-Rubalcava ML, Hernández-Bautista BE, Jiménez-Estrada M, González MC, Glenn AE, Hanlin RT, Hernández-Ortega S, Saucedo-García A, Muria-González JM, Anaya AL. Naphthoquinone spiroketal with allelochemical activity from the newly discovered endophytic fungus Edenia gomezpompae . Phytochemistry 2008; 69: 1185-1196
  • 76 Macías-Rubalcava ML, Ruiz-Velasco-Sobrino ME, Meléndez-González C, King-Díaz B, Lotina-Hennsen B. Selected phytotoxins and organic extracts from endophytic fungus Edenia gomezpompae as light reaction of photosynthesis inhibitors. J Photochem Photobiol B 2014; 138: 17-26
  • 77 González MC, Anaya AL, Glenn AE, Macías-Rubalcava ML, Hernández-Bautista BE, Hanlin RT. Muscodor yucatanensis, a new endophytic ascomycete from Mexican chakah, Bursera simaruba . Mycotaxon 2009; 110: 363-372
  • 78 González MC, Glenn AE, Hanlin RT, Macías Rubalcava ML, Hernández Bautista BE, Anaya AL. Acremonium camptosporum isolated as an endophyte of Bursera simaruba from Yucatan Peninsula, Mexico. Mycotaxon 2016; 131: 211-225
  • 79 Strobel G. Muscodor species-endophytes with biological promise. Phytochem Rev 2011; 10: 165-172
  • 80 Macías-Rubalcava ML, Hernández-Bautista BE, Oropeza F, Duarte G, González MC, Glenn AE, Hanlin RT, Anaya AL. Allelochemical effects of volatile compounds and organic extracts from Muscodor yucatanensis, a tropical endophytic fungus from Bursera simaruba . J Chem Ecol 2010; 36: 1122-1131
  • 81 Qadri M, Nalli Y, Jain SK, Chaubey A, Ali A, Strobel GA, Vishwakarma RA, Riyaz-Ul-Hassan S. An insight into the secondary metabolism of Muscodor yucatanensis: Small-molecule epigenetic modifiers induce expression of secondary metabolism-related genes and production of new metabolites in the endophyte. Microb Ecol 2017; 73: 954-965
  • 82 Meléndez-González C, Muria-González MJ, Anaya AL, Hernández-Bautista BE, Hernández-Ortega S, González MC, Glenn AE, Hanlin RT, Macías-Rubalcava ML. Acremoxanthone E, a novel member of heterodimeric polyketides with a bicyclo[3.2.2]nonene ring, produced by Acremonium camptosporum W. GAMS (Clavicipitaceae) endophytic fungus. Chem Biodivers 2015; 12: 133-147
  • 83 García-Méndez MC, Macías-Ruvalcaba NA, Lappe-Oliveras P, Hernández-Ortega S, Macías-Rubalcava ML. Phytotoxic potential of secondary metabolites and semisynthetic compounds from endophytic fungus Xylaria feejeensis strain SM3e-1b isolated from Sapium macrocarpum . J Agric Food Chem 2016; 64: 4255-4263
  • 84 Macías-Rubalcava ML, García-Méndez MC, King-Díaz B, Macías-Ruvalcaba NA. Effect of phytotoxic secondary metabolites and semisynthetic compounds from endophytic fungus Xylaria feejeensis strain SM3e-1b on spinach chloroplast photosynthesis. J Photochem Photobiol B 2017; 166: 35-43
  • 85 Sánchez-Ortiz BL, Sánchez-Fernández RE, Duarte G, Lappe-Oliveras P, Macías-Rubalcava ML. Antifungal, anti-oomycete and phytotoxic effects of volatile organic compounds from the endophytic fungus Xylaria sp. strain PB3f3 isolated from Haematoxylon brasiletto . J Appl Microbiol 2016; 120: 1313-1325
  • 86 Sánchez-Fernández RE, Díaz D, Duarte G, Lappe-Oliveras P, Sánchez S, Macías-Rubalcava ML. Antifungal volatile organic compounds from the endophyte Nodulisporium sp. strain GS4d2II1a: a qualitative change in the intraspecific and interspecific interactions with Pythium aphanidermatum . Microb Ecol 2016; 71: 347-364
  • 87 Ulloa-Benítez Á, Medina-Romero YM, Sánchez-Fernández RE, Lappe-Oliveras P, Roque-Flores G, Duarte G, Herrera T, Macías-Rubalcava ML. Phytotoxic and antimicrobial activity of volatile and semi-volatile organic compounds from the endophyte Hypoxylon anthochroum strain Blaci isolated from Bursera lancifolia (Burseraceae). J Appl Microbiol 2016; 121: 380-400
  • 88 Medina-Romero YM, Roque-Flores G, Macías-Rubalcava ML. Volatile organic compounds from endophytic fungi as innovative postharvest control of Fusarium oxysporum in cherry tomato fruits. Appl Microbiol Biotechnol 2017; 101: 8209-8222
  • 89 Del Valle P, Figueroa M, Mata R. Phytotoxic eremophilane sesquiterpenes from the coprophilous fungus Penicillium sp. G1-a14. J Nat Prod 2015; 78: 339-342

Correspondence

Prof. Dr. Rachel Mata
Departamento de Farmacia
Facultad de Química
Universidad Nacional Autónoma de México
Ciudad de México
México   
Phone: + 52 55 56 22 52 89   
Fax: + 52 55 56 22 53 29   

  • References

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  • 12 Mata R, Cristians S, Escandón-Rivera S, Juárez-Reyes K, Rivero-Cruz I. Mexican antidiabetic herbs: valuable sources of inhibitors of alpha-glucosidases. J Nat Prod 2013; 76: 468-483
  • 13 Venieraki A, Dimou M, Katinakis P. Endophytic fungi residing in medicinal plants have the ability to produce the same or similar pharmacologically active secondary metabolites as their hosts. Hell Plant Protect J 2017; 10: 51-66
  • 14 Rivera-Chávez J, González-Andrade M, González MC, Glenn AE, Mata R. Thielavins A, J and K: alpha-glucosidase inhibitors from MEXU 27095, an endophytic fungus from Hintonia latiflora . Phytochemistry 2013; 94: 198-205
  • 15 Sakemi S, Hirai H, Ichiba T, Inagaki T, Kato Y, Kojima N, Nishida H, Parker JC, Saito T, Tonai-Kachi H, VanVolkenburg MA, Yoshikawa N, Kojima Y. Thielavins as glucose-6-phosphatase (G6Pase) inhibitors: producing strain, fermentation, isolation, structural elucidation and biological activities. J Antibiot (Tokyo) 2002; 55: 941-951
  • 16 Mudur SV, Gloer JB, Wicklow DT. Sporminarins A and B: antifungal metabolites from a fungicolous isolate of Sporormiella minimoides . J Antibiot (Tokyo) 2006; 59: 500-506
  • 17 Clapp-Shapiro WH, Burgess BW, Giacobbe RA, Harris GH, Mandala S, Polishook J, Rattray M, Thornton RA, Zink DL, Cabello A, Diez MT, Martín I, Peláez F. Antifungal agent from Sporomiella minimoides. US Patent US5801172A; 1998.
  • 18 Leyte-Lugo M, Figueroa M, González MC, Glenn AE, González-Andrade M, Mata R. Metabolites from the endophytic fungus Sporormiella minimoides isolated from Hintonia latiflora . Phytochemistry 2013; 96: 273-278
  • 19 Rangel-Grimaldo M, Rivero-Cruz I, Madariaga-Mazón A, Figueroa M, Mata R. alpha-Glucosidase inhibitors from Preussia minimoides double dagger. J Nat Prod 2017; 80: 582-587
  • 20 Song F, Wu SH, Zhai YZ, Xuan QC, Wang T. Secondary metabolites from the genus Xylaria and their bioactivities. Chem Biodivers 2014; 11: 673-694
  • 21 Macías-Rubalcava ML, Sánchez-Fernández RE. Secondary metabolites of endophytic Xylaria species with potential applications in medicine and agriculture. World J Microbiol Biotechnol 2016; 33: 15
  • 22 Rivera-Chávez J, Figueroa M, González MC, Glenn AE, Mata R. alpha-Glucosidase inhibitors from a Xylaria feejeensis associated with Hintonia latiflora . J Nat Prod 2015; 78: 730-735
  • 23 Frisvad JC, Houbraken J, Popma S, Samson RA. Two new Penicillium species Penicillium buchwaldii and Penicillium spathulatum, producing the anticancer compound asperphenamate. FEMS Microbiol Lett 2013; 339: 77-92
  • 24 Del Valle P, Martínez AL, Figueroa M, Raja HA, Mata R. Alkaloids from the fungus Penicillium spathulatum as alpha-glucosidase inhibitors. Planta Med 2016; 82: 1286-1294
  • 25 Verastegui-Omana B, Rebollar-Ramos D, Pérez-Vásquez A, Martínez AL, Madariaga-Mazón A, Flores-Bocanegra L, Mata R. alpha-Glucosidase inhibitors from Malbranchea flavorosea . J Nat Prod 2017; 80: 190-195
  • 26 Mata R, Figueroa M, González-Andrade M, Rivera-Chávez JA, Madariaga-Mazón A, Del Valle P. Calmodulin inhibitors from natural sources: an update. J Nat Prod 2015; 78: 576-586
  • 27 Figueroa M, González-Andrade M, Sosa-Peinado A, Madariaga-Mazón A, Del Río-Portilla F, González Mdel C, Mata R. Fluorescence, circular dichroism, NMR, and docking studies of the interaction of the alkaloid malbrancheamide with calmodulin. J Enzyme Inhib Med Chem 2011; 26: 378-385
  • 28 González-Andrade M, Benito-Pena E, Mata R, Moreno-Bondi MC. Biosensor for on-line fluorescent detection of trifluoroperazine based on genetically modified calmodulin. Anal Bioanal Chem 2012; 402: 3211-3218
  • 29 González-Andrade M, Figueroa M, Rodríguez-Sotres R, Mata R, Sosa-Peinado A. An alternative assay to discover potential calmodulin inhibitors using a human fluorophore-labeled CaM protein. Anal Biochem 2009; 387: 64-70
  • 30 González-Andrade M, Mata R, Madariaga-Mazón A, Rodríguez-Sotres R, Del Pozo-Yauner L, Sosa-Peinado A. Importance of the interaction protein-protein of the CaM-PDE1A and CaM-MLCK complexes in the development of new anti-CaM drugs. J Mol Recognit 2013; 26: 165-174
  • 31 Gonzalez-Andrade M, Rivera-Chavez J, Sosa-Peinado A, Figueroa M, Rodriguez-Sotres R, Mata R. Development of the fluorescent biosensor hCalmodulin (hCaM)L39C-monobromobimane(mBBr)/V91C-mBBr, a novel tool for discovering new calmodulin inhibitors and detecting calcium. J Med Chem 2011; 54: 3875-3884
  • 32 González-Andrade M, Rodríguez-Sotres R, Madariaga-Mazón A, Rivera-Chávez J, Mata R, Sosa-Peinado A, Del Pozo-Yauner L, Arias-Olguín II. Insights into molecular interactions between CaM and its inhibitors from molecular dynamics simulations and experimental data. J Biomol Struct Dyn 2016; 34: 78-91
  • 33 Velázquez-López I, León-Cruz E, Pardo JP, Sosa-Peinado A, González-Andrade M. Development of new hCaM-Alexa Fluor® biosensors for a wide range of ligands. Anal Biochem 2017; 516: 13-22
  • 34 Kong Au T, Chow Leung P. Identification of the binding and inhibition sites in the calmodulin molecule for ophiobolin A by site-directed mutagenesis. Plant Physiol 1998; 118: 965-973
  • 35 Rai MK, Tiwari VV, Irinyi L, Kövics GJ. Advances in taxonomy of genus Phoma: polyphyletic nature and role of phenotypic traits and molecular systematics. Indian J Microbiol 2014; 54: 123-128
  • 36 Domsch KH, Gams W, Anderson TH. Compendium of soil Fungi, Vol. 1. London: Academic Press (London) Ltd.; 1980
  • 37 Neumann Brebaum S, Boland GJ. First report of Phoma herbarum and Phoma exigua as pathogens of dandelion in southern Ontario. Plant Dis 1999; 83: 200
  • 38 Rivero-Cruz JF, García-Aguirre G, Cerda-García-Rojas CM, Mata R. Conformational behavior and absolute stereostructure of two phytotoxic nonenolides from the fungus Phoma herbarum . Tetrahedron 2000; 56: 5337-5344
  • 39 Rivero-Cruz JF, Macias M, Cerda-García-Rojas CM, Mata R. A new phytotoxic nonenolide from Phoma herbarum . J Nat Prod 2003; 66: 511-514
  • 40 Martínez-Luis S, Pérez-Vásquez A, Mata R. Natural products with calmodulin inhibitor properties. Phytochemistry 2007; 68: 1882-1903
  • 41 Schnick PJ, Boland GJ. 2,4-D and Phoma herbarum to control dandelion (Taraxacum officinale). Weed Sci 2017; 52: 808-814
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Fig. 1 Secondary metabolites isolated from endophyte MEXU 27095.
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Fig. 2 Secondary metabolites isolated from endophyte P. minimoides.
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Fig. 3 Secondary metabolites isolated from endophyte X. feejeensis.
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Fig. 4 Secondary metabolites isolated from coprophilous P. spathulatum.
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Fig. 5 Secondary metabolites isolated from M. flavorosea.
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Fig. 6 Secondary metabolites isolated from plant pathogen P. herbarum.
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Fig. 7 Secondary metabolites isolated from coprophilous G. polythrix.
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Fig. 8 Secondary metabolites isolated from marine-derived Emericella sp. MEXU 25379 and A. stromatoides.
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Fig. 9 Secondary metabolites isolated from endophyte MEXU 26343.
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Fig. 10 Secondary metabolites isolated from entomopathogen I. fumosorosea.
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Fig. 11 Secondary metabolites isolated from saprophyte P. lilacinum.
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Fig. 12 Secondary metabolites isolated from coprophilous M. aurantiaca.
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Fig. 13 Secondary metabolites isolated from marine-facultative Aspergillus sp. MEXU 27854.
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Fig. 14 Secondary metabolites isolated from endophyte E. gomezpompae.
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Fig. 15 Secondary metabolites isolated from endophyte A. camptosporum MEXU 26354.
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Fig. 16 Secondary metabolites isolated from endophyte X. feejeensis SM3e-1b.
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Fig. 17 Secondary metabolites isolated from coprophilous Penicillium sp. G1-a14.