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: Eukarya
(unranked): Opisthokonta
Kingdom: 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.
• Selected Anti-Fungal
Drugs
Amphotericin B

• 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-(4-
trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene and 1,6-
diphenylhexatriene] 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:

• 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 :
• 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 5-

flourodeoxyuridinemonophosphate 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.