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Lostatin-Lovastatin-DRUGS FROM FUNGI


Fungi make an extraordinarily important contribution to managing disease in humans and other animals. At the beginning of the 21st century, Fungi were involved in the industrial processing of more than 10 of the 20 most profitable products used in human medicine. Two anti-cholesterol statins, the antibiotic penicillin and the immunosuppressant cyclosporin A are among the top 10. Each of these has a turn over in excess of $1 billion annually. Drug discovery continues. The following have recently been approved for human use: Micafungin is an antifungal agent; mycophenolate is used to prevent tissue rejection; Rosuvastatin is usd to reduce cholesterol; and cefditoren as an antibiotic.

Fungi are extremely useful organisms in biotechnology. Fungi construct unique complex molecules using established metabolic pathways. Different taxa produce sets of related molecules, each with slightly different final products. Metabolites formed along the metabolic pathway may also be biologically active. In addition, the final compounds are often released into the environment. Manipulation of the genome, and environmental conditions during formation of compounds, enable the optimisation of product formation.

On the negative side, single isolates of fungi in manufacture may lose their capacity to form or release the target molecules. Indeed, the target compound may only be expressed under specific conditions, or at a specific point in the life cycle of the fungus. It is amazing that so many biologically active compounds have been discovered and taken to the point where they are medically important. Indeed, attempts to ‘discover’ new and exciting molecules remains the core activity of many research groups.

The role of fungi was established early in history. Yeasts have been used in the making of bread and alcohol since the beginning of civilisation. LINK In modern times, the discovery of penicillin marked the beginning of a new approach to microbial diseases in human health. More recent approaches include the application of hydrophobins to surfaces leading to biocompatibility of implants, and to emulsion formation improving drug delivery. The established importance of fungi is being expanding way beyond their capacity to transform and protect.

Antibiotics From Fungi

In 1941, penicillin from the fungus Penicillium chrysogenum was first used successfully to treat an infection caused by a bacterium. Use of penicilin revolutionised the treatment of pathogenic disease. Many formally fatal diseases caused by bacteria became treatable, and new forms of medical intervention were possible.

When penicillin was first produced, the concentration of active ingredient was approximately 1 microgram per ml of broth solution. Today, improved strains and highly developed fermentation technologies produce more than 700 micrograms per ml of active ingredient.

In the early broths, several closely related molecules were present. These molecules are beta lactam rings fused to five-membered thiazolidine rings, with a side chain. The side chain can be chemically modified to provide slightly different properties to the compound.

The natural penicillins have a number of disadvantages. They are destroyed in the acid stomach, and so cannot be used orally. They are sensitive to beta lactamases, which are produced by resistant bacteria, thus reducing their effectiveness. Also, they only act on gram positive bacteria.

Modifications to manufacturing conditions have resulted in the development of oral forms. However, antibiotic resistance among bacteria is becoming an extremely important aspect determining the long-term use of all antibiotics.

Cephalosporins also contain the beta lactam ring. The original fungus found to produce the compounds was a Cephalosporium, hence the name. As with penicillin, the cephalosporin antibiotics have a number of disadvantages. Industrial modification of the active ingredients has reduced these problems.

The only broadly useful antifungal agent from fungi is griseofulvin. The original source was Penicillium griseofulvin. Griseofulvin is fungistatic, rather than fungicidal. It is used for the treatment of dermatophytes, as it accumulates in the hair and skin following topical application.

More recently, several new groups have been developed. Strobilurins target the ubihydroquinone oxidation centre, and in mammals, the compound from fungi is immediately excreted. Basidiomycetes, especially from tropical regions, produce an enormous diversity of these compounds.

Sordarins are structurally complex molecules that show a remarkably narrow range of action against yeasts and yeast-like fungi. The compounds inhibit protein biosynthesis and so may become important agents against a number of fungal pathogens of humans.

Echinocandins are cyclic peptides with a long fatty acid side chain. They target cell wall formation. Semi-synthetic members of the group of compounds include pneumocandins which are in use in humans.

Immune Suppressants

Cyclosporin A is a primary metabolite of several fungi, including Trichoderma polysporum and Cylindrocarpon lucidum. Cyclosporin A has proven to be a powerful immunosuppressant in mammals, being widely used during and after bone marrow and organ transplants in humans. Cyclosporin A is a cyclic peptide consisting of 11 mainly hydrophobic amino acids. Its inhibition of lymphocytes was first discovered during the 1970s. Subsequently, the mode of action was elucidated.

Cyclosporin A binds to a cytosolic protein called cyclophilin. Cyclophilin is found amongst many different organisms and its form appears highly conserved. Cyclophilin is involved with folding the protein ribonuclease. However, the Cyclosporin A/cyclophilin complex also binds to calcineurin. Calcineurin dephosphorylates a transcription factor, thereby triggering transcription of numerous genes associated with T cell proliferation. When the complex binds to calcineurin, T cell proliferation is suppressed. The inhibition of T cells proliferation results in the suppression of the activation process associated with invasion by foreign bodies. As a consequence, transplant tissues, which are foreign bodies, are not rejected.

Calcineurin is also highly conserved amongst phylogenetically diverse organisms. In fungi such as the human pathogen Cryptococcus neoformans, calcineurin is necessary for recovery from cell cycle arrest, growth in hypertonic solutions and regulation of the calcium pump. Thus the interaction of the Cyclosporin A/cyclophilin complex with calcineurin in Cryptococcus will result in death of the pathogen. However, in humans, cyclosporin also suppresses the immune system. The side effect is an unacceptable risk, and Cyclosporin A is not used as a fungicide in humans at present.

Gliotoxins also have immunological and antibiotic activity. Produced by many fungi including Aspergillus fumigatus, gliotoxins belong to a class of compounds called epipolythiodioxopiperazines. The antibiotic activity is widely recognised and considered uninteresting. However, its effect on the immune system, especially macrophages, is being re-examined.

A wide range of other compounds with antibiotic activity are also known. They have been rejected for use in medicine because of unwanted side effects, or instability of the active compound.

Ergot Alkaloids

Claviceps purpurea is the causal agent of St Anthonies fire, a scourge of the middle ages when ergots contaminated flour. LINK The ergots contain many alkaloids. Their effects are quite variable. They act on the sympathetic nervous system resulting in the inhibition of noradrenaline and sclerotin, causing dilation of blood vessels. They also act directly on the smooth muscles of the uterus causing contractions, thus their early use to induce abortion. Their strongest effect is intoxication, caused by lysergic acid amides, one of which is the recreational (and illegal) drug, LSD.


Ergot alkaloids have a number of medicinal uses. Perhaps the most widespread use is in the treatment of migraines. The vasodilator activity reduces tension during an attack. The drugs also reduce blood pressure, though with untoward side effects. Alkaloids are now produced in culture by strains of C. fusiformis and C. paspalii.

Pleurotus ostreatus, the oyster mushroom, naturally contains up to 2.8% lovastatin on a dry weight basis


Aspergillus terreus, a soil-borne fungus, produces a secondary metabolite called lovastatin and Phoma sp producessqualestatin. Statins have been used to reduce or remove low density lipoproteins from blood vessels in humans. In fact, the compounds all act via an enzyme in the liver that makes cholesterol, lovastatin inhibits HMG CoA reductase and squalestatin inhibits squalene synthase. By blocking the enzyme, the body removes cholesterol complexes from the inside of blood vessels. This has the effect of reducing or removing blockages in arteries, and thereby reducing the chance of a heart attack, strokes and diabetes.

In addition, statins have been implicated in attracting stem cells to damaged tissues. The stem cells then appear to regenerate the tissue.

Some statins induce problems. One form of the drug has been associated with muscle wastage. Others appear to lack side effects and have been recommended for wide spread use to control heart disease.

Compactin and lovastatin, natural products with a powerful inhibitory effect on HMG-CoA reductase, were discovered in the 1970s, and taken into clinical development as potential drugs for lowering LDL cholesterol.

In 1982, some small-scale clinical investigations of lovastatin, a polyketide-derived natural product isolated from Aspergillus terreus, in very high-risk patients were undertaken, in which dramatic reductions in LDL cholesterol were observed, with very few adverse effects. After the additional animal safety studies with lovastatin revealed no toxicity of the type thought to be associated with compactin, clinical studies continued.

Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987. It was the first statin approved by the FDA.

Lovastatin is also naturally produced by certain higher fungi, such as Pleurotus ostreatus (oyster mushroom) and closely related Pleurotusspp. Research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals has been extensive, although the effect has been demonstrated in a very limited number of human subjects.

In 1998, the FDA placed a ban on the sale of dietary supplements derived from red yeast rice, which naturally contains lovastatin, arguing that products containing prescription agents require drug approval. This ban was subsequently rescinded, in light of law that upholds that natural products are not patentable. Judge Dale A. Kimball of Federal District Court, granted a motion by Cholestin’s manufacturer, Pharmanex, that the agency’s ban was illegal under the 1994 Dietary Supplement Health and Education Act and should be lifted.


Anke T & Thines E. (2007) Fungal metabolites as lead structures for agriculture. In: Exploitation of Fungi. Eds: Robson GD, van West P, Gadd GM. CUP.

Suryanarayanan TS et al (2009) Fungal endophytes and bioprospecting. Fungal Biology Reviews 23, 9-19.

Wainwright M. (1995) An Introduction to Fungal Biotechnology. Wiley, Chichester.

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