Fungal Diversity

, 50:3 | Cite as

Fifty years of drug discovery from fungi

Review

Abstract

For the past 50 years, fungal secondary metabolites have revolutionized medicine yielding blockbuster drugs and drug leads of enormous therapeutic and agricultural potential. Since the discovery of penicillin, the first β-lactam antibiotic, fungi provided modern medicine with important antibiotics for curing life threatening infectious diseases. A new era in immunopharmacology and organ transplantation began with the discovery of cyclosporine. Other important drugs or products for agriculture derived from or inspired by natural products from fungi include statins, echinocandins and strobilurins. Moreover, fungal biotransformation of steroids for the industrial production of steroidal hormones represents one of the key successes in biotechnology. Given that estimations of fungal biodiversity exceed by far the number of already identified species, chances to find hitherto unidentified fungal species and novel bioactive fungal products are still high. Thus, further compounds with medicinal or agricultural potential from less investigated fungal taxa can be expected in the years to come.

Keywords

Drug discovery Fungi Bioactive metabolites 

Introduction

Natural products are known from almost all living organisms and are thought to serve their producing organisms by improving their fitness and competitive strength (Williams et al. 1989; Gunatilaka 2006; Osbourn and Lanzotti 2009). However, their immense importance in medicine and agriculture is likewise fascinating, considering the fact that such implications are far beyond their raison d’être (Koehn 2009). Since ancient times, biologically active secondary metabolites, often in the form of plant extracts, have been used by man as traditional medicines and in some cases also as natural poisons (Larsen et al. 2005). Up till now, the tremendous contribution of natural products in drug discovery and development is evident. This is not limited to isolation and direct therapeutic application of pharmacologically active secondary metabolites, but also extends to semi-synthetic modifications of lead structures from nature for activity enhancement, as well as to synthetic development of structural mimics inspired by nature (Strobel and Daisy 2003; Newman and Cragg 2007).

In spite of advances in combinatorial chemistry as a tool for drug discovery, literature reviews demonstrate that natural products account for around 50% of approved new drugs in the years 2000–2006, of which a significant proportion (31.4%) are biologicals or vaccines. Considering a larger time span, the number rises to 70% including natural products, drugs based thereon, or natural products mimics. In the period 1981–2006, only around 30% of the approved antiinfective drugs, and 22.2% of anticancer drugs were synthetic in origin (Newman and Cragg 2007). In view of that, natural products have been the traditional pathfinders showing enormous structural diversity incomparable to the largest combinatorial databases, which outnumber natural products but fail to provide a comparable structural diversity (Strobel and Daisy 2003). Since there are still many unexplored resources from nature, an enormous chance for finding new or less investigated organisms and thereby new lead structures still exists. Such findings would satisfy not only the growing need for new antibiotics and chemotherapeutic agents, but could also yield better agrochemicals with higher activity, lower toxicity, and less environmental impact than many of the currently used products.

The potential of fungal natural products in drug discovery

Higher fungi have a long history of use in folk medicine, especially in the Asian countries, and their study has become a matter of great significance in recent decades (Lindequist et al. 2010). Investigations on their secondary metabolites have mostly been aiming to isolate bioactive compounds as potential lead structures for the development of new drugs, products for crop protection, and even in cosmetics (Anke and Thines 2007; Hyde et al. 2010). For instance, the medicinal higher fungus Ganoderma lucidum has been used since ancient times to treat hepatitis, hypertension, hypercholesterolemia and gastric cancer (Tang and Zhong 2004). It was found to possess antimicrobial and anti-HIV activities (Yoon et al. 1994; El-Mekkawy et al. 1998), as well as hepatic and renal protective effects (Shieh et al. 2001). The main active ingredients ganoderic acids belong to the lanostane-type triterpenes (Kubota et al. 1982; Tang and Zhong 2004). In specific, ganoderic acid T and ganoderic acid Me showed considerable anticancer activities (Hosokawa et al. 1983; Nishitoba et al. 1987; Tang et al. 2006). A further example are Cordyceps mushrooms which are highly esteemed in Traditional Chinese Medicine for the treatment of respiration, pulmonary, renal, liver, and cardiovascular diseases, as well as for treating hyposexuality and hyperlipidemia (Khan et al. 2010). Recently, their use in the treatment of immune disorders and as an adjunct to modern cancer therapies has been reported (Holliday and Cleaver 2008). Extracts of C. sinensis and C. militaris showed significant anticancer activities by immune system modulation and by inducing cell apoptosis (Khan et al. 2010). Furthermore, cordycepin (3′-deoxyadenosine) was isolated from extracts of both Cordyceps species and showed potent anticancer activity. Due to structural similarity to adenosine, cordycepin is used as a precursor for cellular RNA biosynthesis. Incorporation of the compound leads to premature termination of RNA synthesis and hence to cell death (Siev et al. 1969). As shown in the examples above, medicinal substances from mushrooms often express promising curative effects which may include antitumor, immune modulating, cardiovascular, antiviral, antibacterial, and antiparasitic activities (Wasser and Weis 1999; Wasser 2002; Poucheretpet et al. 2006; Spiteller 2008; Jiang et al. 2011).

The investigation of microfungi for bioactive metabolites was initiated by the discovery of penicillin G from Penicillium notatum by Alexander Fleming more than 80 years ago (1928). Since then fungal microorganisms became a hunting ground for novel drug leads (Strobel and Daisy 2003; Larsen et al. 2005). In the following years several further antimicrobial agents of fungal origin such as griseofulvin (Grove et al. 1952) and cephalosporin C (Newton and Abraham 1955) were discovered. This stimulated pharmaceutical companies to sample and screen large collections of fungal strains especially for antibiotics (Butler 2004). Consequently, promising novel natural product leads were isolated. Many of these compounds can be produced in large quantities and at a reasonable cost by fermentation employing wild type or genetically altered fungi. In the early years of drug discovery from microfungi, the organisms were mainly isolated from soil samples. As the investigations of soil fungi started to show a reduced hit-rate of novel compounds, attention was drawn to other, alternative sources including marine microorganisms (Paz et al. 2010; Blunt et al. 2011; Rateb and Ebel 2011) and endophytic fungi associated with plants (Zhang et al. 2006; Aly et al. 2010; Xu et al. 2010; Kharwar et al. 2011). It is hoped that by probing fungi from new or less investigated ecological niches new lead structures for drugs or agrochemicals will eventually emerge. The search for new drug candidates is still pressing since adequate cures for many old as well as newly emerging diseases, such as cancer, drug-resistant pathogenic microbes, or parasitic protozoans, are urgently needed. As microorganisms occupy almost every niche on earth (Strobel 2002), scientists speculate that many undescribed species exist in unexplored habitats, where the incidence of finding microorganisms that produce novel bioactive constituents is high (Hawksworth and Rossman 1997).

Important drugs and drug leads from fungi

The value of biopharmaceuticals was estimated to be 41 billion dollars in the global market, with a growth rate of 21% over the period 2004–2008, including great profits for fungal derived drugs, for example 1.7 billion for amoxicillin and 1.4 billion dollars for cyclosporine during the above mentioned 4 years period (Smith and Ryan 2009). In the following section the most important drugs and drug leads from fungal natural products discovered over history are presented (Table 1). The drugs are listed in chronological order according to the time of their discovery. Presented compounds were mainly chosen based on their commercial importance for the pharmaceutical or agricultural industries. Some of the presented compounds have revolutionized the therapy of life threatening diseases, represent new therapy concepts, or are currently undergoing development based on clinically proven therapeutic effects. In addition, fungal biotransformation of steroids for the production of therapeutically important steroidal hormones and analogues is also discussed.
Table 1

Important drugs and drug leads from fungi

Drugsa

Uses

Sales

References

Penicillins

Antibiotics

15 billion dollars (2002)

Abraham et al. 1941

Cephalosporins

Newton and Abraham 1955

Elander 2003

Griseofulvin

Antifungal

31.1 million dollars (2007)

Grove et al. 1952

IMS Health 2008

Fusidic acid

Antibiotic

No data available

Godtfredsen et al. 1962b

Crosbie 1963

Cyclosporine

Immuno-suppressive

1.4 billion dollars (2004–2008)

Shaw 1989

Smith and Ryan 2009

Mevastatin

Antilipidemic

15.5 billion dollars (2004)

Endo et al. 1976

Lovastatin

Negishi et al. 1986

Synthetic analogues e.g. atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin

Buckland et al. 1989

IMS Health 2005

Strobilurin A and B

Agricultural fungicides

600 million dollars (1999)

Anke et al. 1977

Synthetic analogues e.g. azoxystrobin, kresoxim-methyl, metominostrobin, trifloxystrobin, picoxystrobin, pyraclostrobin

Bartett et al. 2001

Echinocandins

Antifungal

No data available

von Benz et al. 1974

Pneumocandins

Schwartz et al. 1989

PF1022A

Anthelmintic

No data available

Sasaki et al. 1992

Semisynthetic analogue emodepside

Scherkenbeck et al. 1998

Harder et al. 2003

Nodulisporic acid A

Insecticidal

No data available

Ondeyka et al. 1997

Semisynthetic analogue N-tert-butyl nodulisporamide

Meinke et al. 2009

Scyphostatin

N-SMase inhibitor

No data available

Tanaka et al. 1997

aIncluding agrochemicals

β-lactam antibiotics

This extensive class of antibiotics includes antibiotic agents containing a β-lactam nucleus in their chemical structure. These include penicillins (penams), cephalosporins (cephems), monobactams, and carbapenems (Holten and Onusko 2000). All of these compounds act by inhibiting the synthesis of the peptidoglycan layer of the bacterial cell wall. In specific the final transpeptidation step is blocked by their irreversible binding to transpeptidases which are also known as penicillin-binding proteins (PBPs). As a result, peptidoglycan precursors accumulate, thus triggering the digestion of existing peptidoglycan by autolytic hydrolases, causing bacterial cell death (Waxman and Strominger 1983).

Already back in 1907 Hermann Staudinger synthesized the first β-lactam by a [2 + 2]cycloaddition reaction of the Schiff base, built from aniline and benzaldehyde, with diphenylketene (Staudinger 1907; Tidwell 2008). In 1928 Alexander Fleming observed that a culture of Staphylococcus aureus was contaminated by a blue-green mold, which inhibited growth of adjacent bacterial colonies. This indicated that the mold, later identified as Penicillium notatum, produced an antibacterial principle named penicillin (Fleming 1980). In the 1940s Howard Florey and Ernst Chain were able to isolate the active ingredient penicillin and produce it on a large scale (Abraham et al. 1941). The structure of penicillin was first proposed in 1943, and remained a matter of debate until 1945 (Abraham 1990). About 10 years later cephalosporin C was identified from cultures of Cephalosporium acremonium (Newton and Abraham 1955). The first β-lactam antibiotics were mainly active against Gram-positive bacteria, however, new generations with broad-spectrum activities against bacterial strains that include also Gram-negative organisms have been developed.

β-Lactam antibiotics, mainly penicillins and cephalosporins, are among the world’s blockbuster drugs achieving worldwide sales of about 15 billion dollars in 2002 (Table 1), which represented around 65% of the world antibiotic market. Attempts to improve the productivity of producing organisms, e.g. Penicillium chrysogenum and Acremonium chrysogenum, and fermentation technologies resulted in considerable cost reduction over the past decades (Elander 2003).

A major problem encountered worldwide in the 21st century is the rising emergence of bacterial resistance to commonly used antibiotics. Bacteria are able to develop resistance towards all classes of currently used antibiotics by a diversity of complex molecular mechanisms, leading scientists to question whether the antibiotic era is approaching its end (Alanis 2005). Development of bacterial resistance to β-lactam antibiotics is usually due to β-lactamases that enzymatically hydrolyse the β-lactam ring. In inherent resistance, genes encoding these enzymes are present in the bacterial chromosome, while in acquired type resistance genes encoding for resistance mechanisms are transmitted horizontally through the conjugation between taxonomically unrelated bacteria (plasmid mediated resistance) (Bush and Jacoby 1997; Alanis 2005). This is a growing health care problem considering that recent studies show an estimated number of over 94,000 methicillin-resistant Staphylococcus aureus infections resulting in over 18,000 deaths per year in the United States (Klevens et al. 2007). Co-administration of β-lactam antibiotics with β-lactamase inhibitors, such as clavulanic acid, is a common approach to overcome bacterial resistance. Bacteria may also develop resistance by altering PBPs, thus inhibiting binding of β-lactams to these altered PBPs. This mode of resistance is observed for methicillin-resistant S. aureus and penicillin-resistant Streptococcus pneumoniae (Dowson et al. 1989; Moisan et al. 2010).

Despite the fact that β-lactam antibiotics are already used since more than 60 years for the treatment of bacterial infections, their importance for the drug market is still high. Intensive studies aiming at the improvement of potency, efficacy, spectrum of activity, activity against resistant pathogens, stability, and pharmacokinetic properties of β-lactam antibiotics are still ongoing. Advances in molecular biology methods helped to identify structural and regulatory biosynthetic genes, opening up new possibilities for metabolic engineering of biosynthetic pathways that are involved in fungal β-lactam biosynthesis (Demain and Elander 1999).

Griseofulvin

Griseofulvin (Fulvicin®, Grifulvin V®, Grisovin FP®, Gristatin®) was one of the first antifungal natural products discovered in filamentous fungi (Grove et al. 1952). The drug is derived from the mold Penicillium griseofulvum and is commonly used to treat fungal infections of the skin, hair, and nails. The fungistatic drug acts by binding to tubulin, thus interfering with microtubule function and inhibiting mitosis (Huber and Gottlieb 1968; Richardson and Warnock 2003). In addition, griseofulvin accumulates in the keratin precursor cells and binds to the new keratin making it highly resistant to fungal invasions. Accordingly, the new growth of tissue is usually free of infection and replaces the infected tissues. The drug has a limited spectrum of action that is almost restricted to dermatophytes, including Epidermophyton floccosum, Microsporum and Trichophyton species (Richardson and Warnock 2003). Annual market sales of griseofulvin oral suspension in the United States were estimated to reach 31.1 million dollars in 2007 (Table 1) (IMS Health 2008).

Griseofulvin strongly inhibits mitosis in fungal cells but inhibition in mammalian cells is only weak. Similar to antimitotic drugs, such as vinca alkaloids and taxanes, it was found to inhibit cell-cycle progression at prometaphase/anaphase of mitosis in human cells by suppressing spindle microtubule dynamics (Ho et al. 2001; Panda et al. 2005). However, griseofulvin is relatively safe at the clinical doses because it mainly accumulates in the keratin layers of the skin, where it exerts its action by inhibiting fungal mitosis at concentrations which are significantly lower than those required to inhibit mitosis in human cells (Brian 1949; Gull and Trinci 1973; Panda et al. 2005). Tumor cells usually contain multiple centrosomes, associated with the formation of multipolar mitotic spindles and chromosome segregation defects, but they might regain mitotic stability by the fusion of multiple centrosomes into two functional spindle poles. In the course of developing tumor-specific targets for the selective eradication of malignant cells, griseofulvin was found to inhibit centrosomal clustering, thus driving tumor cells with supernumerary centrosomes to undergo multipolar mitoses, and subsequently, apoptosis. In contrast, diploid fibroblasts and keratinocytes with a normal centrosome content were not affected (Ho et al. 2001; Rebacz et al. 2007). Based on the lack of significant toxicity in humans, the use of griseofulvin as an adjuvant in combination with other anticancer drugs was suggested (Ho et al. 2001; Panda et al. 2005; Bergstralh and Ting 2006).

Fusidic acid

Fusidic acid, a steroid-like antibiotic, was isolated for the first time in 1962, from the fermentation broth of Fusidium coccineum, parasitic on a Veronica plant (Plantaginaceae), and showed potent antibiotic activity against S. aureus including penicillin-resistant strains (Godtfredsen et al. 1962a; Crosbie 1963). Due to its strong antibiotic activity, the compound was introduced to clinical use in the same year of its discovery as an oral preparation (Godtfredsen et al. 1962b), and later in 1968 as a parenteral preparation (Anderson 1980).

Studies to determine the mechanism of action of this drug revealed that it inhibits bacterial protein synthesis by interfering with the elongation factor G (EF-G), an essential bacterial protein that enters the ribosome in GTP- or GDP-bound form and promotes translocation on the ribosome following peptide bond formation. Fusidic acid inhibits the GTPase function of EF-G by binding to the EF-G/GTP or GDP/ribosome complex thereby stabilizing it and preventing further elongation (Tanaka et al. 1968; Cundliffe 1972; Yaskowiak and March 1995). Furthermore, in high concentration fusidic acid was reported to inhibit the binding of aminoacyl-tRNA to the donor site on ribosomes (Otaka and Kaji 1973).

The compound evoked great interest to further screen other fungal strains for its production, as well as to evaluate and investigate possibilities to broaden the spectrum of its antimicrobial activity (von Daehne et al. 1979; Verbist 1990). Additionally, intensive studies were undertaken to assess the pharmacokinetic properties of fusidic acid and its preparations (Wise et al. 1977; Guenthner and Wenzel 1984; Reeves 1987; MacGowan et al. 1989; Faber and Rosdahl 1990; Taburet et al. 1990; Verbist 1990). Of great interest is the fact that fusidic acid still provides high antistaphylococcal activity, despite more than 40 years of clinical use in many parts of the world (Barry and Jones 1987; Pohold et al. 1987; Verbist 1990; Falagas et al. 2008). The clinical importance of fusidic acid is primarily due to its activity against resistant bacterial strains, such as penicillin- and methicillin-resistant S. aureus. In addition, it shows in vitro activity against many gram-positive bacteria, including Nocardia spp., Mycobacteriumn tuberculosis, Neisseria spp. and some anaerobic bacterial pathogens (Godtfredsen et al. 1962b; Black and McNellis 1971; Leigh 1974; Stirling and Goodwin 1977; Miles and Moyes 1978; Falagas et al. 2008). Fusidic acid is able to penetrate infection sites and clear staphylococcal infections where other apparently appropriate antibiotics have failed, as in cases of osteomyelitis and endocarditis (Penman 1962; Taylor and Bloor 1962; Ravn 1967; Whitby 1999). Moreover, fusidic acid penetrates the aqueous and vitreous humour of the non inflamed eye and has hence been used, in combination with other agents, for the treatment of postoperative intraocular infections (Chadwick and Jackson 1969; Williamson et al. 1970; Kanski 1974). Combinations of fusidic acid with other antibiotics were investigated. When taken in combination with rifampicin it showed moderate synergy (Zinner et al. 1981), and with vancomycin it was effective for the treatment of methicillin-resistant S. aureus pneumonia (Welte and Pletz 2010).

Even though several fusidic acid derivatives and structurally related steroid antibiotics with a vast array of chemical modifications were synthesized, only 24,25-dihydrofusidic acid exhibited equivalent activity to the parent compound fusidic acid (Godtfredsen et al. 1966; von Daehne et al. 1979).

Cyclosporine

A new era in immunopharmacology began with the discovery of cyclosporine, obtained from Tolypocladium inflatum, in 1971 (Pritchard 2005). The source fungus was isolated from a soil sample collected by Sandoz scientists at Hardangervidda, Norway, in 1969 (Shaw 1989). Cyclosporine is a cyclic peptide composed of 11 amino acids, one of which being a D-amino acid rarely encountered in nature.

Upon interaction of an antigen-presenting cell with a T-cell receptor, the cytoplasmic level of calcium increases in the T-cell, thus activating calcineurin. Calcineurin is a protein phosphatase, which is responsible for activating T-cells, through the dephosphorylation of the transcription factor NF-AT (nuclear factor of activated T-cells). The activated NF-AT triggers the transcription of genes encoding for interleukin 2 and related cytokines (Crabtree 1999; Yamashita et al. 2000). Cyclosporine prevents the dephosphorlyation of the transcription factor NF-AT by binding to the mitochondrial matrix protein, cyclophilin D, thus inhibiting calcineurin activity (Ganong 2005). Consequently, the production of TNF alpha and other pro-inflammatory mediators such as interleukin 2 is reduced, resulting in a decreased function of effector T-cells.

Cyclosporine was the first immunosuppressive drug that allowed selective immunoregulation of T-cells without exhibiting excessive toxicity. It is used as an immunosuppressant during organ transplantations (Borel and Kis 1991; Butler 2004), and is now widely exploited in organ and tissue transplantation surgery, to prevent rejection following bone marrow, kidney, liver and heart transplantations. Its discovery revolutionized organ transplant surgery, considerably increasing survival rates in transplant patients (Dewick 2006). Furthermore, the use of cyclosporine to treat patients suffering from ulcerative colitis and not responding to steroidal treatment has been reported (Lichtiger et al. 1994). Annual market sales of cyclosporine were estimated to reach 1.4 billion dollars over the period 2004–2008 (Table 1) (Demain 2000; Smith and Ryan 2009).

In addition to the previously described mechanism, binding of cyclosporine to cyclophilin D, an integral component of the mitochondrial permeability transition pore (MPTP), inhibits mitochondrial permeability transition (MPT) (Elrod et al. 2010). Due to the important role of MPT in regulating necrotic cell death, MPT inhibitors may be of great promise in the treatment of diseases, such as ischemia-reperfusion injury, trauma, and neurodegenerative ailments (Waldmeier et al. 2003). For instance, in the treatment of cardiac hypertrophy, cyclosporine binding to cyclophilin D prevents MPTP opening, thus decreasing the release of apoptogenic proteins, such as cytochrome C, from the intermembrane space to initiate apoptotic signaling, and regulating improper MPTP opening. The latter is caused by the accumulation of mitochondrial Ca2+, as the heart tries to compensate for the disease condition through increasing the intracellular Ca2+ to enhance the contractility cycling rates (Whelan et al. 2010). As Ca2+ levels decrease a reversal of cardiac hypertrophy is achieved (Mott et al. 2004).

Statins

The antilipidemic statin compounds represent another group of important fungal derived drugs. Statins are the most potent cholesterol-lowering agents available. Some statins are fermentation derived, for instance the first statin compound mevastatin, isolated from Penicillium citrinum (Endo et al. 1976), as well as lovastatin (Mevacor®), isolated from Monascus ruber (Negishi et al. 1986) and later from Aspergillus terreus (Buckland et al. 1989). Other members of this group of compounds are synthetic analogues derived from the natural fungal metabolites, such as the major selling synthetic statins (lipitor®, crestor® and livalo®). By 2010 a number of statins were introduced to the market, including atorvastatin (Lipitor®, Torvast®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®) (Sweetman 2009). Two lipid-regulating drugs of this class, atorvastatin and simvastatin, feature prominently in the top ten drugs by cost, reflecting the widespread implementation of clinical guidelines and recommendations relating to coronary heart disease. Overall statin sales reached 15.5 billion dollars in 2004 (6.6% of total drug sales) (Table 1) showing a 12% increase over 2003, 29% over 2001, and 46% over 2000 (Demain 2000; IMS Health 2005).

Statins lower cholesterol level in the human body by reversible competitive inhibition of the rate-limiting enzyme hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase in the mevalonate pathway of cholesterol biosynthesis (Alberts 1988), thus reducing total and low-density lipoprotein cholesterol levels. This activity is due to the close structural resemblance of the statin acid form with the natural enzyme substrate HMG-CoA (Alberts et al. 1980). As high blood cholesterol levels contribute to the incidence of coronary heart disease, statins are of potential value in treating high-risk coronary patient (Butler 2004; Dewick 2006; Lewington et al. 2007).

Following a long-term treatment with statins, a 60% decrease in the number of cardiac events, such as heart attack or sudden cardiac death, and a 17% reduced risk of stroke was reported (Law et al. 2003). Researchers assume that statins decrease the incidence of stroke via several mechanisms including retardation of atherosclerosis progression, plaque stabilization, or improved endothelial function. In addition, a significant reduction of both systolic and diastolic blood pressure and a blunt hypertensive response to a cold pressor test were observed. Accordingly, the drugs may cause vasodilation and fall in blood pressure by modulating the sympathetic and endothelial regulation of vasomotor tone (Furberg 1999). Another study showed that administration of an intensive statin therapy, using 40 mg/d of rosuvastatin, to patients with preexisting coronary disease reduced low-density lipoprotein cholesterol (LDL-C) to 53.2% while raising high-density lipoprotein cholesterol (HDL-C) by 14.7% (Nissen et al. 2006). This intensive statin therapy was well tolerated, and the decreased LDL-C and increased HDL-C levels resulted in significant regression in atheroma burden, thus recommending the administration of such therapies for high-risk patients with established coronary disease prevention of atherosclerosis (Nissen et al. 2006; Taylor et al. 2011).

Strobilurins

The first naturally occurring strobilurins, strobilurins A and B, were isolated from the mycelium of the basidiomycete, Strobilurus tenacellus, a small edible agaric which grows on decaying cones of Purus. Both compounds had no antibacterial activities but inhibited the growth of a variety of filamenteous fungi and yeasts (Anke et al. 1977). The strobilurins are β-methoxyacrylic acid derivatives that have been isolated from a large number of Basidiomycete genera, including Strobilurus, Oudemansiella, Xerula, Hydropus, Mycena, Filoboletus, Crepidotus, and Cyphellopsis, in addition to an Ascomycete, Bolinea lutea (Anke et al. 1977, 1983; Anke 1995; Fredenhagen et al. 1990; Weber et al. 1990). They showed potent antifungal activity against phytopathogenic fungi at very low concentrations of 10−7–10−8 M, which together with their low toxicity towards mammals and plants made them promising lead compounds for the synthesis of agricultural fungicides (Anke 1995).

The compounds exert their action by suppressing fungal cell respiration. In specific, they bind to the ubiquinol-oxidation center of the mitochondria1 bc1 segment of cytochromes, whose function is to generate the proton gradient used for ATP synthesis and to transfer electrons to nitrogenase, hence blocking electron transfer resulting in prevention of mycelial growth and spore germination (Becker et al. 1981; Houchins and Hind 1983; Von Jagow et al. 1986; Sauter et al. 1999; Dayan et al. 2009). A complete reversion of this action is possible by addition of glucose, allowing the cells to compensate for the depletion of ATP, caused by inhibition of oxidative phosphorylation, by glycolysis (Anke et al. 1979; Anke 1995). It appears that the ecological role of strobilurins is to secure nutrient supplies for the producing fungi from competing fungi that live on the same natural substrate (Anke 1995; Dayan et al. 2009).

Intensive studies examining the structure of natural strobilurins and analysing structural activity relationship aspects allowed synthesis of fungicidal analogues with enhanced stability, efficacy, and a broader spectrum of action (Beautement and Clough 1987; Zakharychev and Kovalenko 1998; Clough 2000). In 1999 annual sales of strobilurin fungicides accounted for around 10% of the global fungicide market reaching nearly 600 million dollars (Table 1) (Bartett et al. 2001). Nowadays, two strobilurin fungicides are on the market, namely azoxystrobin from Zeneca, sold as Amistar® for cereals, Quadris® for grape vines, and Heritage® for turf, as well as kresoxim-methyl from BASF. Both were first published in 1992 (Ammermann et al. 1992; Godwin et al. 1992) and introduced to the market 4 years later (Clough 2000). Meanwhile, azoxystrobin is registered for use on 55 crops in 49 countries representing one of the world’s leading fungicides with total sales of about 290 million dollars in 1998 and 415 million dollars in 1999 (Clough 2000; Bartett et al. 2001). Kresoxim-methyl is mainly available as mixture with other fungicides, for example for use on cereals in combination with fenpropimorph or epoxiconazole which are sold as Brio® and Allegro®, respectively (Clough 2000). In the following years studies were performed by various agrochemical companies to develop other strobilurin fungicides. In 1999 metominostrobin was introduced to the market by Shionogi (Hayase et al. 1995), and trifloxystrobin by Novartis (Margot et al. 1998), which was then sold in 2000 to Bayer CropScience, whereas in 2001 picoxystrobin (Syngenta) (Godwin et al. 2000), and pyraclostrobin (BASF) (Ammermann et al. 2000) were launched.

Unfortunately, resistance to strobilurins developed in populations of plant pathogenic fungi only 2 years after introducing them to the market because they are single-target compounds (Appel and Felsenstein 2000; Ishii et al. 2001). Accordingly, it is advisable to license novel fungicides only in mixtures with other fungicide(s) having different target sites in order to avoid emergence of fungicide resistance (Lesemann et al. 2006).

Echinocandins

Echinocandins are antifungal drugs that act by blocking the synthesis of β-glucan polymers, essential components of the fungal cell wall, by a non-competitive inhibition of the enzyme 1,3-β-D-glucan synthase (Denning 1997; Morris and Villmann 2006a, b). This selective mode of action to fungal cell walls leads to minimal toxicity in human cells. Fungal echinocandin metabolites discovered in the 1970’s were the lead compounds and templates for the clinically used semisynthetic antifungal drugs. They are lipo-peptides consisting of large cyclic peptides linked to long chain fatty acids.

Echinocandin B was one of the first echinocandins, isolated from an Aspergillus nidulans culture in 1974 (von Benz et al. 1974; Keller-Juslen et al. 1976). The compound was chemically modified to yield cilofungin, the first clinically applied compound of this class, in the 1980s and LY303,366 (Lilly) in the 1990s (Denning 1997). Later in 1989 researchers at Merck were able to isolate a closely related group of compounds, from Zalerion arbicola, which they named pneumocandins (Schwartz et al. 1989), from which the clinical candidate L-743,872 was developed (Denning 1997). The term pneumocandins indicates two pathogens against which this class of compounds is active, which are Pneumocystis carinii and Candida spp. (Denning 1997).

Echinocandin B and pneumocandin B, isolated from Aspergillus rugulovalvus and Glarea lozoyensis, respectively, were the lead compounds and templates for the semisynthetic antifungal drugs caspofungin (Cancidas®), the first approved semisynthetic echinocandin, anidulafungin (Eraxis®), and micafungin (Mycamine®) (Butler 2004). All three agents are approved for their use in the treatment of oesophageal candidiasis, candidaemia and other forms of invasive candidiasis. Micafungin is the only echinocandin licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutropenia. Furthermore, combination therapy including a member of the echinocandin group of compounds proved to be promising in the treatment of aspergillosis. All echinocandins have low oral bioavailability, good distribution into tissues, but poor into the CNS and eye, and thus are administered intravenously (Chen et al. 2011).

PF1022A

Infections by parasitic nematodes are widely spread in plants, animals and humans. Approximately 1.300 million people are infected by Ascaris lumbricoides and 1.000 million people by the hookworms Ancylostoma duodenale or Necator americanus. In addition, nematode parasites cause massive economic losses of crop plants and livestock (Mehlhom 1988). Increasing nematode resistance and slow degradation in the soil are among the greatest problems encountered during the use of anthelmintics (Scherkenbeck et al. 1998).

A new class of anthelmintic agents was introduced in the early 1990s with the discovery of the cyclodepsipeptide PF1022A. The compound was isolated during a screening study for new anthelmintic antibiotics, using Ascaridia galli as a test organism, from cultures of Mycelia sterilia (Sasaki et al. 1992). A. galli is a parasitic roundworm, of the phylum Nematoda, which inhabits the small intestine of poultry causing ascaridiasis (Griffiths 1978). The producing strain PF1022 was isolated from Camellia japonica collected in Ibaraki Prefecture, Japan (Sasaki et al. 1992). PF1022A contains 4N-Methyl-L-leucines, 2 D-lactic acids and 2 D-phenyllactic acids which are arranged to form a cyclic octadepsipeptide with alternating L-D-L-configuration (Scherkenbeck et al. 1998; Harder et al. 2003).

Primary biological tests showed that 2 mg/kg of PF1022A oral administration to chicken exhibited potent anthelmintic activities against A. galli (Scherkenbeck et al. 1998). The observed activity was dose dependent with no toxic effect to the host animals (Scherkenbeck et al. 1998; Dornetshuber et al. 2009). In addition, PF1022A showed no activity against Gram-positive and Gram-negative bacteria, yeasts and other fungi at a dose of 100 μg/mL (Sasaki et al. 1992). Further studies reported in vitro activity against the intestinal nematode Angiostrongylus cantonensis (10−7 g/mL), as well as in vivo activity against Toxocara canis or Ancylostoma caninum (1.0 mg/kg) (Scherkenbeck et al. 1998). Furthermore, activities against Haemonchus contortus, Trichostrongylus colubriformis, and Ostertagia ostertagi were also reported (Conder et al. 1995). Studies of structure-activity relationships showed that an increase in lipophilicity improves the bioavailability of the corresponding cyclooctadepsipeptides. Furthermore, anthelmintic activities of compounds with similar lipophilicities are highly affected by the nature of the N-methyl amino acids. In specific (L)-N-methyl leucine residues were found to be essential for in vivo activity (Scherkenbeck et al. 1998). Based on these data tetra- and mono-thionated analogues were synthesized in the following years, some of which having an improved broader spectrum of activity against parasitic nematodes (Jeschke et al. 2001; Lee et al. 2002), such as emodepside, the semisynthetic bis-paramorphonyl-derivative of PF1022A, patented by Fujisawa Pharmaceutical Co. Ltd (Japan), in 1993. Both, PF1022A and emodepside, are active against benzimidazole-, levamisole- or ivermectin-resistant nematodes in sheep and cattle, indicating a different mode of action compared to the latter compounds (Harder et al. 2003; von Samson-Himmelstjerna et al. 2005). Currently, emodepside is marketed in combination with praziquantel, another anthelmintic drug, for the treatment of roundworm, hookworms and tapeworm parasites in cats under the trade name Profender® (Bayer HealthCare). The compounds act by binding to the latrophilin-like transmembrane receptor, thus inhibiting pharyngeal pumping of the nematodes in a concentration dependent manner with an IC50 value of about 4 nM (Harder et al. 2003; Dornetshuber et al. 2009). Based on these data their use in the treatment of human Ascaris lumbricoides infections is considered, which may be of great future promise (Hagel and Giusti 2010).

Nodulisporic acid

Nodulisporic acid A and its analogues are structurally complex insecticidal fungal metabolites isolated from Nodulisporium sp. endophytic in the Hawaiian plant Bontia daphnoides (Ondeyka et al. 1997; Hensens et al. 1999). The parent compound, nodulisporic acid A, was found to exhibit systemic efficacy against fleas, where it modulates an invertebrate specific glutamate-gated ion channel. Studies were conducted to develop an analogue to be administered orally to dogs. This resulted in identification of N-tert-butyl nodulisporamide. The compound is a potent and effective oral agent to be given once monthly for the control of fleas and ticks on dogs and cats. Its efficacy was compared to that of the topical agents fipronil and imidacloprid, where the compound showed favorable results. Multidose studies carried out over 3 months corroborated the in vivo ectoparasiticidal efficacy of N-tert-butyl nodulisporamide. In addition, they confirmed that the compound shows no obvious mammalian toxicity. Tissue distribution studies in mice using [14C]-labels indicated that adipose beds serve as ligand depots, thus contributing to the long terminal half-lives of this compound (Shoop et al. 2001; Meinke et al. 2009).

Scyphostatin

Scyphostatin was discovered as a component of a mycelial extract of Trichopeziza mollissima, in 1997 (Tanaka et al. 1997; Nara et al. 1999a). The fungus was first identified as Dasyscyphus mollissimus, but identification was later revised as the generic name Dasyscyphus was no longer accepted by present taxonomy (Nara et al. 1999a). The compound represents the first low molecular weight inhibitor of the membrane-bound neutral sphingomyelinase (N-SMase) enzyme ever discovered, either from natural sources or by chemical synthesis. Furthermore, scyphostatin is the most potent among the few known small molecule inhibitors of this enzyme with an IC50 value of 1.0 μM (Nara et al. 1999a, b). This potent activity attracted considerable attention of scientists since such inhibitors are believed to be of potential use in the treatment of inflammation, autoimmune diseases, and cancer (Kolesnick and Golde 1994; Shida et al. 2008). N-SMase hydrolyses sphingomyelin to yield phosphocholine and ceramide (Ago et al. 2006), the latter being significantly involved in mediating and regulating many key cellular responses including cell proliferation, survival, and death (Hannun and Obeid 2002).

Accordingly, several studies were conducted in the beginning of 2000 to determine the absolute configuration of scyphostatin and to synthesize related inhibitors, with low molecular weight, primarily as molecular tools to investigate the enzymatic mechanism of the various isoforms of sphingomyelinases (Saito et al. 2000; Hoye and Tennakoon 2000; Izuhara and Katoh 2001; Runcie and Taylor 2001). It was found that scyphostatin inhibits shear stress-induced but not ceramide-induced activation of Src-like kinase and concomitant tyrosine phosphorylation of plasma membrane protein, thus confirming the hypothesis on the key role of N-SMase and its downstream product ceramide in mechanosignaling (Czarny and Schnitzer 2004). However, in spite of potent activity and great therapeutic potential, to date scyphostatin has not been introduced to clinical use.

Biotransformation of steroids by fungi

Steroidal hormones can be ranked among the most extensively marketed pharmaceutical products (Fernandes et al. 2003). They are widely used in medicine as anti-inflammatory, progestational, diuretic, anabolic, contraceptive, antiandrogenic, progestational, anti-fungal, anticancer agents in some forms of breast and prostate cancer, replacement agents in adrenal insufficiencies, as well as in the treatment of osteoporosis, the prevention of coronary heart disease, the prevention and treatment of infection by HIV, as active ingredients in anti-obesity agents, and last but not least as oral contraceptives (Zeelen 1990; Mahato and Garai 1997; Fernandes et al. 2003).

Steroidal hormones usually exert their therapeutic action by binding to respective intracellular receptors, the formed steroid hormone-receptor complex acting then as a transcription factor in the regulation of gene expression (Rupprecht and Holsboer 1999). Furthermore, neurosteroids that are synthesized by glial cells and concentrated in the central and peripheral nervous systems were reported to act as allosteric modulators of neurotransmitter receptors by altering neuronal excitability through direct interaction with the cell surface (Rupprecht and Holsboer 1999; Mellon and Griffin 2002). Examples include dehydroepiandrosterone and its sulphate, progesterone, pregnenolone and their sulfate derivatives, 17β-estradiol, allopregnanolone, synthetic alphoxolone and ganaxolone (Robel and Baulieu 1995; Maksay et al. 2001; Mellon and Griffin 2002). Pharmaceutical applications as memory-enhancers, anxiolytics, antidepressives, as well as neuroprotective agents were reported for such compounds (Markowski et al. 2001; Mellon and Griffin 2002).

The use of biocatalysts for the synthesis of such complex steroidal molecules is of particular interest as highly specific regio- and stereo-selective reactions are needed (Fernandes et al. 2003). Since the early 1950s, the importance of fungal biotransformation of steroids has been recognized for industrial applications. The first biotransformation reactions, patented in 1937, were involving reduction of the 17-keto group (Schoeller 1937; Mamoh 1937) and oxidation of the Δ5-3β-hydroxyl function to a Δ4-3-oxo function (Koester 1937). Yet the importance of fungal biotransformation of steroids for industrial applications was first realized in the early 1950s when the process of 11α-hydroxylation of progesterone by a Rhizopus was patented (Murray and Peterson 1952). At the time, standardized chemical procedures for the preparation of progesterone from available plant steroids, such as diosgenin and stigmasterol, were well established. However, for the production of corticosteroids introduction of an oxygen function at C-11 of progesterone was needed. In contrast to uneconomical chemical methods, it was possible in a single-step high-yielding procedure to prepare 11α-hydroxyprogesterone by fungal biotransformation. Accordingly, the process was immediately utilized for industrial production. Since then fungal biotransformation reactions of steroids have been intensely investigated, resulting in several hydroxylation, dehydrogenation and sterol side-chain cleavage reactions for the production of steroidal hormones and their analogues that are industrially employed (Mahato and Mukherjee 1984; Fernandes et al. 2003).

Fungal biotransformation by hydroxylation at 11α-, 11β-, and 15α-positions of steroidal precursors is well established for the production of adrenal cortex hormones and their analogues (Fernandes et al. 2003). Rhizopus spp. and Aspergillus spp. are able to carry out 11α-hydroxylations (Petrič et al. 2010; Samanta and Ghosh 1987), Curvularia spp. and Cunninghamella spp. hydroxylate at 11β-position (Sonomoto et al. 1981; Manosroia et al. 2007), and Penicillium spp. at 15α-position (Irrgang et al. 1997). Introduction of an oxygen function at C-11 was found to be essential for anti-inflammatory activity (Sedlaczek 1988).

Another well established method for the preparation of androstanes is the fungal degradation of the C-17 saturated side chain of commonly available sterols, such as cholesterol, sitosterol, campesterol, mainly by Aspergillus spp. (Viola et al. 1983; Mostafa and Zohri 2000; Sallam et al. 2005; Malaviya and Gomes 2008).

Research in this area is aiming, on one side, at the development of high-yield processes for industrial application (Mahato and Banerjee 1985). On the other side, preparation of new steroidal analogues with potential therapeutic uses and improved properties, in comparison to their natural counterparts, such as increased potency, longer half-lives in the blood stream, simpler delivery methods, and reduced side effects, is also an interesting scope (Fernandes et al. 2003). Meanwhile, identification of the fungal enzymes responsible for the biotransformation reactions was possible (Ahmed et al. 1996; Shkumatov et al. 2002), yet the use of whole cells rather than enzymes as biocatalysts is considered more economical due to the additional costs of enzyme isolation, purification and stabilization (Bortolini et al. 1997).

Recently, interest in investigating endophytic fungi and their potential use as biocatalysts for the chemical transformation of natural products and drugs has arisen, as they have shown capabilities for stereospecific modification of chemical compounds and for the production of known or novel enzymes facilitating such modifications. For instance, a study reported the biotransformation of (−)-grandisin, a tetrahydrofuran lignan, by the endophytic fungus Phomopsis sp., obtained from Viguiera arenaria, yielding a new compound with similar trypanocidal activity as its natural precursor (Verza et al. 2009). In another study, several endophytic fungal strains were able to biomimic mammalian metabolism of thioridazine, a phenothiazine neuroleptic drug, via stereoselective kinetic biotransformation reactions (Borges et al. 2007). However, despite the high potential of such microorganisms with respect to availability of useful strains and the wide range of reactions accomplished by them, studies to use endophytes as biocatalysts in food and pharmaceutical industries are just starting (Pimentel et al. 2011).

Conclusion

In spite of the tremendous number of natural products and natural product derived drugs available on the market for different medical and agricultural applications, intensive research in this area is still required to meet the growing need for new and better drugs and drug leads. The discovery of many bioactive metabolites, such as the β-lactams, which were developed over the years to clinically useful medications, dates back more than 45 years ago (Walsh 2003; Singh and Barrett 2006). The emergence of drug-resistant pathogens or drug-resitant cancer cells to currently available drugs is a worldwide vexing problem of public concern. In the last two decades, the problem has escalated with the development of multidrug resistance in many bacterial pathogens that cause human diseases. Fortunately, it is still possible to combat resistant strains with other available drugs having different modes of action or drug combinations targeting several sites.

It is well known that only a small fraction of the estimated fungal biodiversity worldwide has been investigated for bioactive compounds. Fungi have the ability to adapt to almost all niches on earth and the possibility to discover novel unprecedented species and new bioactive compounds derived from them is great. Accordingly, more extensive collections of fungal species, and further improvements of culturing methods are needed. These attempts would facilitate chemical investigation of fungal species for bioactive secondary metabolites, which may fulfil the urging need for new therapies worldwide.

Notes

Acknowledgment

Continued support by BMBF to P.P. is gratefully acknowledged.

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© Kevin D. Hyde 2011

Authors and Affiliations

  1. 1.Heinrich-Heine-Universität Düsseldorf, Institut für Pharmazeutische Biologie und BiotechnologieDüsseldorfGermany

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