Fungi

0 FUNGI A fungus is a eukaryotic organism that is a member of the kingdom

Fungi . The fungi are a monophyletic group, also called the Eumycota ,that is phylogenetically distinct from the morphologically similar slime molds (myxomycetes) and water molds (oomycetes). The fungi are heterotrophic organisms possessing a chitinous cell wall, with the majority of fungal species growing as multicellular filaments called hyphae forming a mycelium; some fungal species also grow as single cells. Sexual and asexual reproduction of the fungi is commonly via spores, often produced on specialized structures or in fruiting bodies. Some species have lost the ability to form reproductive structures, and propagate solely by vegetative growth. Yeasts, molds, and mushrooms are examples of fungi. The fungi are more closely related to animals than plants, yet the discipline of biology devoted to the study of fungi, known as mycology, often falls under a branch of botany.

Fungi Fossil range: Early Devonian - Recent (but see text)

Clockwise from top left: Amanita muscaria, a basidiomycete; Sarcoscypha coccinea, an ascomycete; black bread mold, a zygomycete; a chytrid; a Aspergillus conidiophore. Scientific classification

Domain: (unranked): Kingdom:

Eukarya Opisthokonta Fungi Subkingdoms/Phyla

Chytridiomycota Blastocladiomycota Neocallimastigomycota Glomeromycota Zygomycota Dikarya Ascomycota Basidiomycota

Diversity Fungi have a worldwide distribution, and grow in a wide range of habitats, including deserts, hypersaline environments, the deep sea, on rocks, and in extremely low and high temperatures. They have been shown to be able to survive the intense UV and cosmic radiation encountered during space travel. Fungi, along with bacteria, are the primary decomposers of organic matter in most if not all terrestrial ecosystems worldwide. Based on observations of the ratio of the number of fungal species to the number of

plant species in some environments, the fungal kingdom has been estimated to contain about 1.5 million species. Around 70,000 fungal species have been formally described by taxonomists, but the true dimension of fungal diversity is still unknown. Most fungi grow as thread-like filaments called hyphae, which form mycelia, while others grow as single cells. Until recently, many fungal species were described based mainly on morphological characteristics, such as the size and shape of spores or fruiting structures, and biological species concepts. The application of molecular tools, such as DNA sequencing and phylogenetic analysis, to study fungal diversity has greatly enhanced the resolution and added robustness to estimates of genetic diversity within various taxonomic groups.

Microscopic structures

Mold covering a decaying peach over a period of six days. The frames were taken approximately 12 hours apart. Though fungi are part of the opisthokont clade, all phyla except for the chytrids have lost their posterior flagella. Fungi are unusual among the eukaryotes in having a cell wall that, besides glucans (e.g., β-1,3-glucan) and other typical components, contains the biopolymer chitin. Many fungi grow as thread-like filamentous microscopic structures called hyphae, and an assemblage of intertwined and interconnected hyphae is called a mycelium. Hyphae can be septate,

i.e., divided into hyphal compartments separated by a septum, each compartment containing one or more nuclei or can be coenocytic, i.e., lacking hyphal compartmentalization. However, septa have pores, such as the doliporus in the basidiomycetes that allow cytoplasm, organelles, and sometimes nuclei to pass through. Coenocytic hyphae are essentially multinucleate supercells. In some cases, fungi have developed specialized structures for nutrient uptake from living hosts; examples include haustoria in plant-parasitic fungi of nearly all divisions, and arbuscules of several mycorrhizal fungi, which penetrate into the host cells for nutrient uptake by the fungus.

Macroscopic structures Fungal mycelia can become visible macroscopically, for example, as concentric rings on various surfaces, such as damp walls, and on other substrates, such as spoilt food (see figure), and are commonly and generically called mould fungal mycelia grown on solid agar media in laboratory petri dishes are usually referred to as colonies, with many species exhibiting characteristic macroscopic growth morphologies and colours, due to spores or pigmentation. Specialized fungal structures important in sexual reproduction are the apothecia, perithecia, and cleistothecia in the ascomycetes, and the fruiting bodies of the basidiomycetes, and a few ascomycetes. These reproductive structures can sometimes grow very large, and are well known as mushrooms.

List of antifungal drugs Antifungals work by exploiting differences between mammalian and fungal cells to kill off the fungal organism without dangerous effects on the host. Unlike bacteria, both fungi and humans are eukaryotes. Thus fungal and human cells are similar at the molecular level. This means it is more difficult to find a weakness in fungi to attack that does not also exist

in human cells - so, if you attack the fungus, you may also attack the human cells the fungus lives on. Consequently, there are often side-effects to some of these drugs. Some of these side-effects can be life-threatening if not used properly.

There are several classes of antifungal drugs.

Polyene antifungals A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. This changes the transition temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. As a result, the cell's contents leak out (usually the hydrophilic contents) and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. (Note: as a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.) Natamycin -- 33 Carbons , binds well to ergosterol. Rimocidin Filipin -- 35 Carbons, binds to cholesterol (toxic). Nystatin Amphotericin B Candicin

Imidazole and Triazole antifungals The imidazole and triazole are synthetic antifungal drugs that inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in humans.

Imidazoles: Miconazole - (Miconazole nitrate). Ketoconazole Clotrimazole - marketed as Lotrimin or Lotrimin AF Econazole Bifonazole Butoconazole Fenticonazole Isoconazole Oxiconazole Sertaconazole - marketed as Ertaczo in North America. Sulconazole Tioconazole

The triazoles are newer, and are less toxic and more effective

Triazoles: Fluconazole Itraconazole Isavuconazole Ravuconazole Posaconazole Voriconazole Terconazole

Allylamines Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis: Terbinafine - marketed as "Lamisil" in North America, Australia, the UK, Germany and the Netherlands. Amorolfine Naftifine - marketed as "Naftin" in North America. Butenafine - marketed as Lotrimin Ultra.

Echinocandins Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase: Anidulafungin Caspofungin Micafungin

Others Benzoic acid - has antifugal properties but must be combined with a keratolytic agent such as in Whitfield's Ointment. Ciclopirox - (ciclopirox olamine) a fungicidal, It is most useful against Tinea versicolour. Tolnaftate - fungicidal, marketed as Tinactin, Desenex, Aftate, as well as other names. Undecylenic acid - organic unsaturated fatty acid derived from natural castor oil, fungistatic as well as anti-bacterial and anti-viral. Flucytosine, or 5-fluorocytosine, is an antimetabolite. Griseofulvin - binds to polymerized microtubules and inhibits fungal mitosis. Haloprogin - discontinued due to the emergence of more modern antifungals with fewer side effects.

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Selected Anti-Fungal Drugs Amphotericin B

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Mechanism of action As with other polyene antifungals, amphotericin B associates with ergosterol, a membrane chemical of fungi, forming a pore that leads to K+ leakage and fungal cell death. Recently, however, researchers found evidence that pore formation is not necessarily linked to cell death .The actual mechanism of action may be more complex and multi-faceted.

Amphotericin B is believed to interact with membrane sterols (ergosterol) to produce an aggregate that forms a transmembrane channel. Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl and amino groups stabilize the channel in its open form, destroying activity and allowing the cytoplasmic contents to leak out. •

Quantitative structure-activity relationships in amphotericin B derivatives The quantitative structure-activity relationships studies of amphotericin B and its 16 semisynthetic derivatives obtained by modification at carboxyl and amino groups have been done. The results of five biological tests were subjected to principal component analysis, a numerical method useful in the investigation of large sets of data. For some compounds, also, interaction with lipidic vesicles was investigated by spectroscopic methods. The results obtained indicate that:

(i)

The presence of positively charged nitrogen atom (protonable or bearing fixed charge) is indispensable for biological activity and antibiotic-sterol interaction;

(ii)

The lack of free carboxyl group in the molecule favours the differentiation between cholesterol and ergosterol containing cells.

Butenafine hydrochloride

Mechanism of Action Butenafine exerts antifungal activity by blocking squalene epoxidation, resulting in inhibition of ergosterol synthesis (antidermatophyte and Sporothrix schenckii activity). In higher concentrations, the drug disrupts fungal cell membranes (anticandidal activity).

Pharmacology Butenafine hydrochloride is an odorless white crystalline powder that is freely soluble in methanol, ethanol, and chloroform, and slightly soluble in water. Like the allylamine antifungals, butenafine works by inhibiting the synthesis of ergosterol by inhibiting squalene epoxidase, an enzyme responsible for the creation of sterols needed in fungal cell membranes. Lacking ergosterol, the cell membranes increase in permeability, allowing their contents to leak out.

Indications Butenafine is indicated for the topical treatment of tinea (pityriasis) versicolor due to M. furfur, as well as athlete’s foot (Tinea pedis), ringworm (Tinea corporis) and jock itch (Tinea cruris) due to E. floccosum, T. mentagrophytes, T. rubrum, and T. tonsurans. It has superior fungicidal activity against this group of fungi when compared to that of terbinafine, naftifine, clotrimazole, and tolnaftate. It also displays superior activity against Candida albicans when compared against terbinafine and naftifine. Butenafine demonstrates low minimum inhibitory concentrations against cryptococcus and aspergillus.

Butenafine is typically available as a 1% topical cream.

Synthesis and structure-activity relationships Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochloride) is an antifungal agent of the benzylamine class that has excellent therapeutic efficacy and a remarkably long duration of action when applied topically to treat various mycoses. Given the lipophilic nature of the molecule, efficacy may be related to an interaction with cell membrane phospholipids and permeabilization of the fungal cell wall. Similarly, high lipophilicity could account for the long duration of action, since fixation to lipids in cutaneous tissues might allow them to act as local depots for slow release of the drug. We have therefore used computer-assisted conformational analysis to investigate the interaction of butenafine with lipids and extended these observations with experimental studies in vitro using liposomes. Conformational analysis of mixed monolayers of phospholipids with the neutral and protonated forms of butenafine highlighted a possible interaction with both the hydrophilic and hydrophobic domains of membrane phospholipids. Studies using liposomes demonstrated that butenafine increases membrane fluidity [assessed by fluorescence polarization of 1-(4trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene and 1,6diphenylhexatriene] and membrane permeability (studied by release of calcein from liposomes). The results show, therefore, that butenafine readily interacts with lipids and is incorporated into membrane phospholipids. These findings may help explain the excellent antifungal efficacy and long duration of action of this drug when it is used as a topical antifungal agent in humans.

Anidulafungin

Anidulafungin or Eraxis (Ecalta in Europe) is an anti-fungal drug manufactured by Pfizer; it was previously known as LY303366. There is preliminary evidence that it has a similar safety profile to caspofungin. It has proven efficacy against oesophageal candidiasis, but its main utility will probably be in invasive Candida infection; it will probably also have application in treating invasive Aspergillus infection. It is a member of the class of anti-fungal drugs known as the echinocandins.

mechanism of action Mechanism of action is by inhibition of (1→3)β-D-glucan synthase, which is an important component of the fungal cell wall.

Pharmacokinetics Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body pH and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment.

Ciclopirox

Ciclopirox olamine (also called Batrafen Loprox, Penlac and Stieprox) is a synthetic antifungal agent for topical dermatologic treatment of superficial mycoses. It is most useful against Tinea versicolor.

Mechanism of action In contrast to the azoles and other antimycotic drugs, the mechanism of action of ciclopirox is only poorly understood.[ However, loss of function of certain catalase and peroxidase enzymes has been implicated the mechanism of action, as well as various other components of cellular metabolism. In a study conducted to further elucidate ciclopirox's mechanism, several Saccharomyces cerevisiae mutants were screened and tested. Results from interpretation of the effects of both the drug treatment and mutation suggested that ciclopirox may exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport

It acts by inhibiting the membrane transfer system by interrupting the Na+ K+ ATPase.It is currently being investigated as an alternative treatment to ketoconazole for seborrhoeic dermatitis as it suppresses growth of the yeast Malassezia furfur. Initial results show similar efficacy to ketoconazole with a relative increase in subjective symptom relief due to its inherent anti-inflammatory properties.

Tolnaftate

Tolnaftate is a synthetic over-the-counter anti-fungal agent. It may come as a cream, powder, spray, or liquid aerosol, and is used to treat jock itch, athlete's foot and ringworm.

Mechanism Although the exact mechanism of action is not entirely known, it is believed to inhibit the squalene epoxidase, an important enzyme in the biosynthetic pathway of ergosterol (a key component of the fungal membrane) in a similar way to allylamines.

Uses Tolnaftate has been found to be generally slightly less effective than azoles when used to treat tinea pedis. It is, however, useful when dealing with Ringworm, especially when passed from pets to humans.

Haloprogin

Haloprogin is an antifungal drug used to treat athlete's foot and other fungal infections. It is marketed in creams under the trade names Halotex, Mycanden, Mycilan, and Polik.

Action

Haloprogin was previously used in 1% topical creams as an antifungal agent. It was marketed over the counter primarily to treat tinea infections of the skin. The mechanism of action is unknown.

Haloprogin had a high incidence of side effects including: irritation, burning, vesiculation (blisters), scaling, and itching. It has since been discontinued due to the emergence of more modern antifungals with fewer side effects.

Haloprogin Top Uses Haloprogin is used to treat skin infections such as athlete's foot, jock itch, ringworm, and other fungal skin infections (candidiasis). This medication is also used to treat a skin condition known as pityriasis (tinea versicolor), a fungal infection that causes a lightening or darkening of the skin of the neck, chest, arms, or legs. Haloprogin is an antifungal that works by preventing the growth of fungus.

Griseofulvin

Structure Activity Relationship:

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Four possible stereoisomers only (+)-enantiomer is active Cl replaced by F → same activity Cl replaced by Br or H → ↓ activity Placement of the halogen on C5 → ↓ activity Replacement of CH3O on ring C with either propoxy or butoxy functions → ↑ activity

Mechanism of action : • •

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Binds to keratin disrupts the cell's mitotic spindle structure cause defective DNA synthesis interferes with tubulin polymerization

Resistance: is due to alteration of the drug's target site, by mutation of ribosome sequences.

Spectrum of activity: 1) Effective against various species of Trichophyton, Microsporum, and Epidermophyton 2) Not effective against candida and bacteria

Flucytosine

It is structurally related to the cytostatic fluorouracil and to floxuridine. It is available in oral and in some countries also in injectable form.

Mechanisms of action Two major mechanisms of action have been elucidated: One is that the drug is intrafungally converted into the cytostatic fluorouracil that undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis and disturbs the building of certain essential proteins. The other mechanism is the conversion into 5flourodeoxyuridinemonophosphate which inhibits fungal DNA synthesis.

Spectrum of susceptible fungi and resistance Flucytosine is active in vitro as well as in vivo against some strains of Candida and Cryptococcus. Limited studies demonstrate that flucytosine may be of value against infections with Sporothrix, Aspergillus, Cladosporium, Exophila, and Phialophora. Resistance is quite commonly seen as well in treatment naive patients and under current treatment with flucytosine. In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.