Biology of FUNgicourses.k-state.edu/fall2003/BIOL/BIOL604/Lectures/PDFs/Lect19.pdf · medicine, acknowledged the fungi as medicine and describes their use for moxa to stimulate specific

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Biology of FUNgi

Lecture 19The Good - fungi in medicine

Another piece of daily trivia

• Did you know that in 1966 SergioLeone directed a medicalmycology educational piecestarring Clint Eastwood?

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Last time,...

• We had several examples of fungi that may haverestructured our landscapes.

• Ophiostoma ulmi and O. novo-ulmi - the DED

• Cryphonectria parasitica - chestnut blight

• Phytophthora ramorum - SOD

• Glomales - the AM

• Epichloë - the tall fescue endophyte

Fungus of the day -Tolypocladium inflatum

Taxonomy: Phylum (subphylum) Ascomycota Order - Clavicipitales (mitotic) Family - Clavicipataceae (mitotic) Common names - -

The fungus of the dayTolypocladium inflatum is theorigin of cyclosporin, a drug thatmay have revolutionized the organtransplanting practices.

Tolypocladium inflatum anamorph andits teleomorph Cordyceps subsessilis.

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Cordyceps subsessilis is extremelyrare, it has been reported only 5-6times in the world.

The point here is that keeping aneye open for the rare fungi canyield great rewards.

Cyclosporin, however, wasacquired from Cordycepsanamorph Tolypocladium.

Tolypocladium inflatum and itsteleomorph Cordyceps subsessilis.


We get back to the Swiss pharmaceutical - Sandoz, whomwe recall from the production of psilocin and LSD.

Sandoz established a practice to collect and isolate fungifrom soil and tissues for bioactive ingredients.

This still is a common-place procedure: pharmaceuticaland biotechnology industries still explore the natural genepools for active compounds.

An example is XENOVA Ltd. They continuebioprospecting and have more than 30 disease specificscreening systems in place. They estimate that they canfind ca 1 useful compound in every 10,000-100,000screened. The present rate is ca 1,000,000 screens peryear; 10-100 new exploitable compounds each year.

Tolypocladium and itsblastoconidial conidiophores

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Anyways, Sandoz did their standard soil isolations fromsamples from Norway in 1970.

One of the samples yielded Tolypocladium strain with newantifungal activity as a result of cyclopeptide.

This compound was promising: it showed low toxicity tomammals, yet it was cytostatic, antiviral and - mostimportantly - immunosuppressive. It had no effect ontumor growth but selectively inhibited multiplication oflymphocytes. Additionally, it had no effect on othersomatic cell divisions; earlier immunosuppressantsblocked all mitotic divisions.

Because lymphocytes are among the main bodies ofimmunodefense system producing specific antibodies,cyclosporin was thought to be promising for organtransplants.

Tolypocladium and itsblastoconidialconidiophores


Sandoz did its profit assessment of the new potential drug. Theyestimated that getting the new product developed and approvedby FDA would take an initial investment of ca $250 million.

Transplant market was too small to return that investment;organ transplanting suffered from poor success rates as previousmedications had dramatically failed.

While being a poor investment in that respect, cyclosporinproved effective against chronic, systemic infections includingrheumatoid arthritis; these diseases are also immune systemmediated.

Despite side-effects (liver damage), low dosage combined withsteroids are used on more than 200,000 transplant patients.Additional uses for other autoimmune diseases are still beingexplored - juvenile diabetes, psoriasis, multiple sclerosis etc.

Tolypocladium and itsblastoconidialconidiophores

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One may ask whether it is a surprise to findsuch active compounds in a member ifClavicipitales. Remember Cordyceps sinensisand Claviceps purpurea, both of which havefound their applications - at least potential - inmedicine. Claviceps purpurea in LSD andmigraine medicine (Ergate, Cafergot andMigril) and Cordyceps sinensis herbalmedicine.

Cordyceps products aresupposed to improve yourcardiovascular performance

Claviceps perithecia and asci

The Good, the Bad, and the Ugly- mushrooms in medicine

The good - beneficial fungi in medicine

Fungi have a long history in herbal medicine.Herbal medicine was all we had until veryrecently.

Hippocrates (455 B.C.), the renowned father ofmedicine, acknowledged the fungi as medicineand describes their use for moxa to stimulatespecific points in serious chronic illnessassociated with kidney or sciatica.

Similarly, Pliny (ca 20-80 A.D.) - the compiler ofancient natural history lore - mentions fungi beingused as remedy. Unfortunately, he uses a term“Agaricum” which leaves the identities of thosethings wide open.

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Dioscorides (ca 20AD), the author of the mostwidely used herbal of all times - La Materia Medica,did not think too highly of shrooms: “ they growamongst rusty nails or rotten rags, or holes ofserpents, or amongst trees properly bearing harmfulfruits.”

To emphasize the importance of La Materia Medica,we should bear in mind that this was the authority inmedicine until 15th century! The Asian history ofusing fungi is far richer: recall usingAphyllophorales, Auriculariales and Agaricales as aremedy to next to anything.

Auricularia auricula, Lentinula edodes andTrametes versicolor - all used as a generalremedy in Asian herbal medicine.



Historically, aphyllophorales were used asabsorbents. There are two very good reasonsfor this. First, they are fibrous and absorbmoisture well. Second, they have beenshown to have some antibiotic effect andinhibit bacterial growth.

Fungi also affect the central nervous system.Remember Psilocybe spp. Some nativecultures in Siberia and north-east Asia usedfly agaric (Amanita muscaria) for thesepurposes.

Fomitopsis pinicola one of theaphyllophorales with antibiotic andabsorbent uses.

Amanita muscaria - a species used inshaman rituals as a mind alteringingredient.


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Is the homeopathic medicinebased on fungi all bogus?

Examples of clinical tests withLentinula edodes, Trametesversicolor, and Plerotusostreatus


In conclusion, many of the fungi that have found uses in traditional medicinestimulate immune function and inhibit tumor growth; assumed to be due to high-molecular weight polysaccharides. The proposed function: the similarity betweenthese compounds and bacterial outer membranes.

Polysaccharides include a sugar-based(mannose, galactose, xylose) polymerand co-valently bound proteins

As a result, the human immune systemis fooled to believe that there is abacterial infection in place leading toactivation of immune responses -increase in macrophage and killer T-cell activity. The immune systemremains at higher alert with the fungi inplay.


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More of the good - fungi in modern medicine

Penicillin: Sir Alexander Fleming’s discovery of firstbiologically produced antibiotic had.

Penicillin is most active against Gram-positivebacteria. As a specifically targeted antibiotic it has avery precise function in bacterial growth andmetabolism. Penicillin interferes with the cross-linking of the peptides in the peptidoglycan synthesisin bacterial cell membranes. As a result of theincomplete cell membrane, the bacterial cells aresusceptible to osmotic lysis.

Sir Alexander Fleming andPenicillium sp.



To be accurate, penicillin does not kill thebacterial cells per se, it just makes themsusceptible to the host organism’s defenses.

Penicillin is usually produced in three steps.1) Continuous flow production of fungalbiomass2) Recovery from filtrate and acyl radicalremoval by penicillin acylase3) Addition of a specific new radical tomodify the characteristics of penicillin.The modification may result in resistance toenvironmental conditions (Penicillin V -stomach acid) or alter the target group(ampicillin - Gram negative bacteria)

Basic structure of penicillin: two aminoacids Cysteine and Valine. The specificcharacteristics of the molecule arealtered by the choice of the acyl radical.

The Good, the Bad, and theUgly - mushrooms in medicine

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The specificity to one or few cellular processes is bothan advantage and disadvantage of many antibiotics.

Targeting a specific group makes the use of theseproducts safe. Unfortunately, it also makes developingresistance easier.

Cephalosporium (nowAcremonium) is the sourceof cephalosporin antibiotic.



For example, we have seen the emergence of MRSA, the methicillin resistantStaphylococcus. This new wave of antibiotic resistant bacteria underlines theimportance of bioprospecting and looking for new active compounds.

Cephalosporin is an example of these. Isolated from Cephalosporium (nowAcremonium) sp. it has shown effective against Gram- bacteria and can bemodified like penicillin.


Antibiotic trials on two bacteria,resistance for one antibioticpresent in both.

Horizontal gene flow and theintense selection pressure increasechanges for new emergingresistant strains

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How are the fungal secondary metabolites withantibiotic activity inactivated, or how does theresistance emerge?

We already talked about penicillin acylase. One ofthe ways it to cleave the compound enzymaticallyand either break the basic structure or remove theradical.Once the enzyme system is in place the trait can behorizontally transferred from one strain to another.However, these enzyme systems too are ratherspecific. This explains the fact that alterations of theradical may make the enzyme non-fitting to thetarget site and make the cleaving with that enzymeimpossible.

Cephalosporium (nowAcremonium) is the sourceof cephalosporin antibiotic.


More of the good - fungi in modernmedicine

The fungi do not only produceantibacterials. We know of at least onefungus-derived fungicide - griseofulvin.First discovered in 1930’s fromPenicillium griseofulvum the fungicidalcompound went unutilized for over twodecades. This may have largely been dueto relatively low frequency of fatal fungalinfections or the fact that 1930’s mighthave been time with focus on bactericidalcompounds.

Penicillium notatum was theoriginal penicillin producingfungus. Others came about.


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Nonetheless, 1950’s changed treatment ofhuman mycoses completely. Griseofulvinhad been tested on fungal diseases of plantsbut was soon determined to be effective alsoin alleviating the symptoms of fungusdiseases in humans and other animals. Forexample, a man with a ringworm infectionfor all his life (60 years!) was completelycured with griseofulvin.

Tinea capitis - the ringworm of the headcan be treated with griseofulvin.


Microsporum audounii - the causalagent of ringworm of Tinea capitis


Griseofulvin was first identified as the “curling factor.” Thegermtubes of fungi, in presence of griseofulvin grew inspirals and curls. It was first assumed that this too was acell wall synthesis inhibitor, more specifically, a chitinsynthesis inhibitor.

Not true! It was later found out that the mode of action withthe griseofulvin was inhibition of α- and β-tubulins intodimers. In brief, griseofulvin appeared to be a antimitoticdrug as well as disrupting the cellular transport processes(via the cytoplasmic microtubules).

Penicillium griseofulvumThe Good, the Bad, and the Ugly

- mushrooms in medicine

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What is the significance of the antibioticssecondary metabolites in fungi? They mayjust be random products that have noevolutionary significance. However, oneshould bear in mind that they may have aserious function. Fungi having absorptivenutrition, and few means to find otherresources, this might just be the ultimatecompetitive tool. Poison your neighbor toassure sole custody of the currentlyavailable source.

Penicillium notatum was the originalpenicillin producing fungus. Otherscame about.


The Good, the Bad, and the Ugly- medical mycology


As a final treat, enter Beano - theantiflatulant.

Containing an enzyme α-d-galactosidase, Beano will digestgalactose in beans for you and keepyou as well as those down wind fromyou happy.

Aspergillus niger and α-d-galactosidasecontaining Beano

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Fungi are good!

• Fungi alert your immune system.

• Fungi let you have a new liver.

• Fungi kill bad bacterial bugs by cell wallsynthesis inhibition.

• Fungi kill bad fungi by inhibiting mitosis.

• Fungi keep air fresh; Beano.

Documents

Biology of FUNgicourses.k-state.edu/fall2003/BIOL/BIOL604/Lectures/PDFs/Lect19.pdf · medicine, acknowledged the fungi as medicine and describes their use for moxa to stimulate specific