Academia Journal of Microbiology Research 3(2): 022-030, December 2015
DOI: 10.15413/ajmr.2015.0101
ISSN 2315-7771
©2015 Academia Publishing
Research Paper
Disruption of fungi cell membranes by polyenes, azoles, allylamines, amino acids
and peptides
Accepted 7th April, 2015
ABSTRACT
Aderiye*, Babatunde I and Oluwole,
Olusola A
Department of Microbiology, Ekiti State
University, Ado-Ekiti, Nigeria.
Corresponding author email:
[email protected],
[email protected], Tel.
+2348033505146
The fungal cell membrane is one of the targets for some groups of antifungal
agents: the polyenes, lipodepsinonapeptides, amino acids and other peptides,
which interferes with the structural integrity of the lipid bilayer. Polyene
antifungals show effectiveness against sterol-containing organisms by interacting
directly with the fungal ergosterol. Amphotericin B exhibits activity against most
species of Candida, Cryptococcus neoformans, most Aspergillus sp., hyaline molds,
Penicillium, Paecilomyces, and Scopulariopsis, dimorphic fungi including
Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and
Paracoccidioides brasiliensis. Nystatin binds to sterols in the cell membrane of
yeasts resulting in electrolyte leakages. Statins are competitive inhibitors of HMGCoA reductase, which is involved in the ergosterol synthesis. The azoles
specifically inhibits the cytochrome P450 enzyme CYP51, resulting in interruption
of membrane synthesis, depletion of ergosterol leading to an increase in toxic
methylated sterol precursors in the cell membrane. The morpholines are synthetic
antifungals and inhibits the reductase and isomerase enzymes in ergosterol
biosynthesis triggering accumulation of dimethyl-lanosterol and depletion of
ergosterol. Aureobasidins are highly lipophilic and act by inhibiting inositol
phosphoceramide (IPC) synthase, critical in fungal sphingolipid biosynthesis
thereby depleting essential sphingolipids in the fungal cells. The lipopeptide iturin
acts
by
increasing
membrane
permeabilization
in
fungal
cell.
Lipodepsinonapeptides produced by Pseudomonas syringae interacts with the
fungal cell membrane by pore formation resulting in fatal electrolytic leakage.
Syringomycins form ion channels in the fungal plasma membrane employing a
novel sphingolipid-modulated channel formation mechanism while Pseudomycin
A alters several membrane functions like membrane potential, protein
phosphorylation, H1-ATPase activity, and cation transport fluxes.
Keywords: Antifungal, azoles, cell membrane, ergosterol, polyenes.
INTRODUCTION
Fungi have fundamental functions in terrestrial ecosystems,
in degradation of organic matter and in nutrient uptake of
plants through mycorrhizal interactions. Fungi are
achlorophyllous, non-motile, eukaryotic organisms with
bodies (thalli) composed of elongating walled filaments
(hyphae). They have a chitinous rigid cell wall as well as
various polysaccharides (1, 4- and α 1, 6-glucans) and an
ergosterol containing cell membrane (Kwon-Chong and
Academia Journal of Microbiology Research; Babatunde and Olusola.
Bennett, 1992; Chapman et al., 2008). They are
heterotrophs, requiring external sources of carbon for
energy and cellular synthesis and have adopted three
different trophic strategies to obtain this carbon, occurring
as saprotrophs, necrotrophs, and biotrophs (Finlay, 2008).
An antifungal agent is a drug that selectively eliminates
fungal pathogens from a host with minimal toxicity to the
host (Baron, 1996). The three major groups of antifungal
agents in clinical use are the azoles, polyenes, and
allylamine/thiocarbamates, with their antifungal activities
based on inhibition of ergosterol synthesis, the
predominant component of the fungal cell membrane
(Parks and Casey, 1996).
Antifungal agents early discovered and used included the
potassium iodide (KI), weak acids, phenol, dyes as well as
the oils (Mercurio and Ewelski, 1993). The success obtained
from their therapeutic use was however limited until
saturated solution of Potassium Iodide (SSKI), was
demonstrated to be active against cutaneous sporotrichosis
although the agent had narrow spectrum (Mercurio and
Ewelski, 1993). The first landmarks recorded in antifungal
therapy was the discovery of Griseofulvin in 1939 (Oxford,
1939; Sheehan et al., 1999), 1944 discovery by Wooley of
the first azole, benzimidazole (Wooley, 1944); 1945 report
on the fungistatic activity by Elson (1945). Also there was
the discovery of the first Polyene macrolide antifungal
(Nystatin) in 1950 which defined modern antifungal era
(Hazen and Brown, 1950; 1951). The challenge however
was the toxicity of these early antifungals to human cells.
Ergosterol, the major sterol in fungal cell membranes, is of
great importance for membrane fluidity (Bowman et al.,
1987). This provides the basis for two types of selective
antifungals, the polyenes, which interact directly with
ergosterol in the membrane, and compounds inhibiting
different steps in ergosterol biosynthesis e.g. azoles,
allylamines, thiocarbamates and morpholine derivatives
(Gooday, 1995). This paper therefore reviews the activities
of this group of antifungals against fungal cell membrane.
Polyenes
The discovery of nystatin (fungicidin; C47H75NO17) and
amphotericin B (AMB or fungizone; C47H73NO17) in the
1950s has led to the isolation and characterization of
numerous antimicrobial agents (Abu-Elteen and Hamad,
2011). Polyene antifungals were developed from the
fermentation of Streptomyces (Whiffen et al., 1946).
Polyene antifungals show effectiveness against organisms
with sterol-containing cell membranes (e.g., yeast, algae,
and protozoa). Ergosterol, the major sterol in fungal cell
membranes but not found in other eukaryotic membranes,
is of great importance for membrane fluidity (Bowman et
al., 1987). Polyenes have large macrolide ring consisting of
023
12–37 carbon atoms closed by an internal ester of lactone
and 6–14 hydroxyl groups distributed at alternate carbon
atoms along the ring. Their uniqueness to fungal cells
provide the basis for the activity of the group of selective
antifungals, the polyenes, which interact directly with
ergosterol in the membrane rather than the cholesterol of
human cell membranes (Nosanchuk, 2006), as well as other
compounds inhibiting different steps in ergosterol
biosynthesis e.g. azoles, allylamines, thiocarbamates and
morpholine derivatives (Gooday, 1995). Gale et al. (1975)
and Kerridge et al. (1976) showed that the stationary-phase
of Candida cells were more resistant to the polyenes than
those at the exponential-phase. This observation was
attributed to the fact that in the exponential-phase cells,
breakdown and re-synthesis of cell wall constituents occurs
at a high rate, resulting in improved polyene access to the
cell membrane. In contrast, the stationary-phase cells
would be expected to break down and synthesize cell wall
at a much lower rate (Kerridge et al., 1976). Also, the fatty
acyl composition of membrane phospholipids influences
the toxicity of polyenes as alteration in the ratio of various
phospholipids may affect the internal viscosity and
molecular motion of lipids within the membrane (AbuElteen and Hamad, 2011).
Amphotericin B
Amphotericin B alongside amphotericin A is a polyene
antifungal produced by the soil actinomycete Streptomyces
nodosus and displays activity against organisms with sterolcontaining cell membranes (Ghannoum and Rice, 1999).
Initially, it was the first line antifungal for aspergillosis but
over the years, its first line use has been reduced though it
is still a preferred drug for most fungal infections (Hall,
2012). It exhibits broad spectrum activity against most
fungi including most species of Candida (Rodriguez-Tudela
et al., 2009), Cryptococcus neoformans, most Aspergillus sp.
(Barry et al., 2000), hyaline molds, including most species
of Penicillium, Paecilomyces, and Scopulariopsis, dimorphic
fungi including Histoplasma capsulatum, Blastomyces
dermatitidis, Coccidioides immitis, and Paracoccidioides
brasiliensis (Hall, 2012). Amphotericin binds to ergosterol
in cell wall membrane of fungi, resulting in alteration of
membrane permeability by forming oligodendromes that
function as pores through which there is a leakage of
cellular contents (Park et al., 2006). Although amphotericin
B has a greater affinity for the fungal ergosterol, it also has
some affinity for binding to the cholesterol of mammalian
cell membranes (Abu-Salah, 1996). Also, the pore formation
with ergosterol has a 100-fold longer half-life than pores
formed after binding cholesterol (Brutyan and McPhie,
1996). The drug demonstrates a concentration-dependent
activity with a long post-antifungal effect (Andes, 2003).
Academia Journal of Microbiology Research; Babatunde and Olusola.
There is also evidence to suggest that amphotericin Bmediated cell killing may be due in part to the oxidizing
properties of the drug that results in the production of
reactive oxygen species and lipid peroxidation of fungal cell
membrane (Brajtburg et al., 1990).
Nystatin is a polyene antifungal agent, obtained from
Streptomyces noursei commonly used for the treatment of
oral and vaginal candidiasis and is the first successful
antifungal agent in therapy. Nystatin has shown activity
against most yeasts, including Candida albicans, C.
parapsilosis, C. tropicalis, C. guilliermondii, C. krusei, C.
glabrata and also against dermatophytes including
Trichophyton rubrum and T. mentagrophytes. Nystatin binds
to sterols in the cell membrane of yeasts thereby increasing
the membrane permeability which allow the release of K+,
sugars and metabolites (Andes, 2003). Disruption of the cell
membrane is believed to be responsible for fungal death,
but modes of action of amphotericin B and nystatin have
differences. Liposomal nystatin is a multilamellar liposomal
formulation of nystatin, which contains nystatin,
dimyristoylphosphatidyl
choline
and
dimyristoylphosphatidyl glycerol in a ratio of 1:7:3 (by
weight) (Dismukes et al., 2003). Nystatin has broad
antifungal activity and is effective in vitro against most
clinically important yeast and mold isolates (Mehta et al.,
1987; Johnson et al., 1998; Oakley et al., 1999; Quindós et
al., 2000; Arikan et al., 2002.)
Statins are competitive inhibitors of HMG-CoA reductase,
which catalyze the conversion of HMG-CoA to mevalonate, a
rate-limiting step in the isoprenoid biosynthetic pathway,
which is involved in the synthesis of cholesterol in humans
and ergosterol in fungi (Stancu and Sima, 2001). Statins
compete with the natural substrate for the enzyme’s active
site, preventing the formation of a functional enzyme
structure with reversible binding (Corsini et al., 1999).
Thus, the effects of statins are connected with the inhibition
of the synthesis of important isoprenoids, e.g. farnesyl
pyrophosphate and geranylgeranyl pyrophosphate, which
are important lipid attachments for the γ subunit of heterotrimeric G-proteins (Liao and Laufs, 2005) and guanosine
triphosphate binding proteins (Liao, 2002: Ghittoni et al.,
2005). Therefore, statins act as inhibitors of some G-protein
actions and Ras or Ras-like signaling, which affect several
important bioprocesses (Cordle et al., 2005). The growth
inhibition effect of statins on yeast cells is related to the
decreasing ergosterol level, which occurs because of the
inactivation of HMG-CoA reductase inactivation by statins
in the isoprenoid biosynthetic pathway (Sun and Singh,
2009). Ergosterol is a main constituent of the lipid layer of
fungal plasma membrane and the antifungal effect might
arise from decreased membrane fluidity in the yeast cells
(Gyetvai et al., 2006). This assumption is confirmed by the
observation that supplementation with ergosterol or
cholesterol reduced the antifungal effect of statins, (Lorenz
024
and Park, 1990; Macreadie et al., 2006). Lovastatin (LOV) is
a hypocholesterolemic statin that acts by inhibiting 3hydroxy-3-methylglutaryl-coenzyme A reductase, which is
the rate-limiting enzyme of the mevalonate pathway (Miida
et al., 2004). LOV induced apoptosis-like cell death in a
Mucor racemosus isolate at relatively high concentrations
(Rose and Linz, 1998). Lorenz and Parks, (1990) found that
the drug lovastatin (mevinolin) was very effective in
lowering the sterol levels of the wild-type yeast
Saccharomyces cerevisiae. The natural statins (e.g. SIM and
LOV) mainly effect their antifungal activity in their active
metabolite forms (hydrolysis of the lactone ring at pH 10),
and they proved to be less effective as pro-drugs (Nyilasi et
al., 2010). Generally, the synthetic statins are more effective
than the natural ones (Galgóczy et al., 2010).
The Azoles
Inhibition of fungal growth by azoles was first described in
the 1940s and the fungicidal properties of N-substituted
imidazoles were described in the 1960s. Since then, several
azoles have been developed to treat various forms of
mycosis (Kavanagh, 2011). The azole and triazole
antifungal drugs comprise the largest and most widely used
class of compounds (Sosa et al., 2010). The azoles also
affect fungal sterols but target the biosynthesis of
ergosterol rather than the end product itself. The azoles
specifically inhibit the cytochrome P450 enzyme CYP51,
which catalyzes the 14-demethylation of lanosterol, an
essential
step
in
the
production
of
sterols
(Georgopapadakou and Walsh, 1999; Edwards et al., 2013),
resulting in interruption of membrane synthesis as well as
a depletion of ergosterol which then leads to an increase in
toxic methylated sterol precursors in the cell membrane.
The action of most azoles is considered fungistatic;
however, recent studies have indicated a fungicidal activity
of micronazole specifically due to accumulation of druginduced reactive oxygen species within the fungal organism
that results in oxidative damage and cell death (CLSI, 2004).
Reports suggest that the primary target of azoles is the
heme protein, which co-catalyzes cytochrome P-450dependent 14a-demethylation of lanosterol (Hitchcock et
al., 1990). Inhibition of 14a-demethylase leads to depletion
of ergosterol and accumulation of sterol precursors,
including 14a-methylated sterols (lanosterol, 4, 14dimethylzymosterol, and 24-methylenedihydrolanosterol),
resulting in the formation of a plasma membrane with
altered structure and function (Hitchcock et al., 1990).
Inhibition of ergosterol biosynthesis has been
demonstrated with miconazole, terconazole, ketoconazole,
and itraconazole in C. albicans, C. glabrata, C. lusitaniae, P.
ovale, T. mentagrophytes, P. brasiliensis, H. capsulatum and
A. fumigatus (Vanden and Marichal, 1990).
Academia Journal of Microbiology Research; Babatunde and Olusola.
There are two classes of azoles, the imidazoles which
contain two nitrogen atoms in the azole ring and include
mainly the topical agents’ e.g. clotrimazole, miconazole, and
ketoconazole. The other groups are the triazoles with three
nitrogen atoms in the azole ring and include fluconazole,
itraconazole, voriconazole, and posaconazole. The newer
azoles like voriconazole and posaconazole have been
developed to overcome the limited efficacy of fluconazole
against Aspergillus spp. and other molds and to improve the
absorption, tolerability, and drug interaction profile of
itraconazole (Kartsonis et al., 2004). Among species the
systemic triazoles vary in their 14 α-demethylase
inhibition, which may in part explain the differences in
antifungal activity in this class. Asides ergosterol
biosynthesis pathway, triazoles have other secondary
targets. Depending on the genus, the affinity for these
secondary targets varies among the agents. For example, in
fluconazole-susceptible C. albicans, fluconazole only
partially inhibits ergosterol and completely blocks
obtusifoliol synthesis, whereas voriconazole completely
inhibits both ergosterol and obtusifoliol synthesis (Sanati et
al., 1997).
Imidazoles
The imidazoles acts by selectively inhibiting the fungal
cytochrome P450 that brings about sterol C-14αdemethylation, resulting in decreased ergosterol synthesis
and disruption of membrane synthesis in the fungal cell
(Stevens et al., 2000). Clotrimazole causes changes in the
fungal cell membrane that result in the leakage of
intracellular compounds outside of the susceptible cell;
clotrimazole may also act to interfere with amino acid
transport into fungus (Pfaller et al., 2004). Clotrimazole
demonstrates fungistatic activity at concentrations of drug
up to 20 mg/ml and may be fungicidal in vitro against C.
albicans and other species of the genus Candida at higher
concentrations; it is active in vitro against the
dermatophytes Trichophyton mentagrophytes, T. rubrum,
Epidermophyton floccosum and Microsporim canis (Voss and
Pauw, 1999). Ketoconazole exhibited activity against
Trichophyton
rubrum,
T.
mentagrophytes,
and
Epidermophyton floccosum, Candida spp. Malassezia furfur
as well as some dimorphic fungi and dematiaceous agents
responsible for chromoblastomycosis (Pfaller et al., 2004).
However, it is highly toxic to mammalian cells and relapse
is common even after seemingly successful treatment.
025
of action with both classes selectively inhibiting the fungal
cytochrome P450 that causing sterol C-14α-demethylation,
and subsequent reduction in ergosterol synthesis and
alteration of membrane synthesis in the fungal cell (Stevens
et al., 2000). Triazoles, however, have less effect on human
sterol synthesis and are metabolized more slowly than
imidazoles (Stevens et al., 2000, Bennett, 2005).
Fluconazole’s range of activity includes C. albicans, most
strains of C. tropicalis, and C. parapsilosis, while most
strains of C. glabrata demonstrate reduced susceptibility. C.
neoformans, Rhodotorula spp. and Saccharomyces spp. are
often susceptible (Pappas et al., 2009). Fluconazole exhibits
greater activity against yeasts than molds with most
Candida sp. (except C. krusei and C. glabrata) and
Cryptococcus neoformans being susceptible. Itraconazole,
another triazole shows wide range of activity against fungal
species like Candida albicans and some other Candida sp,
active against Aspergillus sp., C. neoformans, the dimorphic
systemic fungi including Histoplasma capsulatum,
Blastomyces
dermatitidis,
Coccidioides
immitis,
Paracoccidioides brasiliensis, Sporothrix schenckii, the
dermatophytes
(Microsporum,
Trichophyton,
Epidermophyton), and many of the dematiaceous moulds
(Pfaller et al., 2009). Unlike fluconazole, Itraconazole is
often considered to be a mould rather than a yeast agent.
Posaconazole is a lipophilic triazole with structure
similar to that of itraconazole. Among the azoles,
posaconazole has a significant role in treatment of
Zygomycotic infections. Posaconazole has a broad spectrum
of activity against yeasts, filamentous, and dimorphic fungi.
This includes Candida sp., Cryptococcus neoformans,
Aspergillus sp., Rhizopus sp., Blastomyces dermatitidis,
Histoplasma
capsulatum,
Coccidioides
immitis,
dermatophytes, and dematiaceous fungi.
Voriconazole inhibits 24-methylene dihydro-lanosterol
demethylase to give increased activity against moulds. The
spectrum of activity of voricnazole, a triazole approved in
2005 includes Candida spp., including fluconazole-resistant
C. krusei and C. glabrata (Pfaller et al., 2006). Other
susceptible yeasts include Cryptococcus neoformans and
Trichosporon beigelii and Saccharomyces cerevisiae (Pfaller
et al., 2006). Its range of activity also includes the
dimorphic systemic fungi e.g. Histoplasma capsulatum,
Blastomyces dermatitidis,
and some strains
of
Pseudallescheria boydii are also susceptible in vitro (TorresRodriguez and Alvarado-Ramirez, 2007).
Allylamines and thiocarbamates
Triazoles
The triazoles and the imidazoles share the same mechanism
The allylamines and the thiocarbamates are antimycotics
that demonstrates exceptionally high activity against
dermatophytes, but have a rather weak effect against
Academia Journal of Microbiology Research; Babatunde and Olusola.
yeasts. They are noncompetitive inhibitors of the enzyme
squalene epoxidase, involved in the cyclisation of squalene
to lanosterol (Petranyi et al., 1984, Georgopapadakou and
Walsh, 1996). Fungal cells affected by these compounds
accumulate squalene with a simultaneous decrease of
ergosterol content, which alters membrane properties
(Polak, 1990). Thiocarbamates and allylamines have a
naphthalene moiety in common, which may be involved in
binding to the enzyme (Polak 1990). They have shown
minimal cross-reactivity with the mammalian enzyme
involved in cholesterol synthesis. The morpholine
amorolfine, a topical antifungal agent for the treatment of
onychomycosis, acts via inhibition of Δ14-reductase and Δ7,
Δ8-isomerase, which are also enzymes in ergosterol
synthesis (Mercer, 1991; Haria and Bryson, 1995).
Terbinafine is an allylamine that reversibly inhibits
squalene epoxidase, an enzyme that acts early in the
ergosterol synthesis pathway. This inhibition produces
both the fungistatic and fungicidal effects on fungal cells.
Terbinafine demonstrates excellent in-vitro fungicidal
activity
against
many
dermatophytes
including
Trichophyton rubrum, T. mentagrophytes, T. tonsurans,
Microsporum canis and Epidermophyton flccosum (Darkes et
al., 2003). It generally demonstrates fungicidal activity
against Candida parapsilosis but it is fungistatic against C.
albicans and other Candida spp. The in vitro spectrum of
activity also includes Aspergillus spp., some dimorphic fungi
and Sporothrix schenckii.
Butenafine is a benzylamine derivative, structurally
similar to the allylamines (e.g., terbinafine), except that a
butyl benzyl group replaces the allylamine group (White,
1999). Butenafine inhibits the conversion of 2, 3oxydosqualene, a reaction catalyzed by the enzyme
squalene epoxidase, thus it subdues ergosterol biosynthesis
by blocking squalene epoxidation. Like the allylamines, the
benzylamine derivatives block an earlier step in ergosterol
biosynthesis than do the azoles. Butenafine is a fungicidal
antimycotic, with activity against the dermatophytes
including
Epidermophyton
floccosum,
Trichophyton
mentagrophytes, T. rubrum, and T. tonsurans (Syed and
Maibach, 2000)
Naftidine is an allylamine that suppresses the
biosynthesis of ergosterol at an earlier stage of the
metabolic pathway than the azoles, independent of
cytochrome P450 enzymes, by inhibiting the activity of
squalene epoxidase. The resulting ergosterol deficiency is
accompanied by an accumulation of squalene in the fungal
cell that leads to cell death (Maeda et al., 1991). Naftidine is
a fungicidal compound with activity mainly against
dermatophytes such as Trichophyton rubrum, Trichophyton
mentagrophytes, T. tonsurans, and Epidermophyton
floccosum, and Microsporum canis, M. audouinii, and M.
gypseum. Fungistatic activity has been shown in vitro
against C. albicans.
026
Morpholines
The morpholines are synthetic antifungals that inhibit the
reductase and isomerase enzymes in ergosterol
biosynthesis. Morpholines are analogues of the high energy
carbo-cationic intermediates formed by these enzymes
(Polak, 1990). Their antifungal activity is mainly due to the
inhibition of the reductase, since it, unlike the isomerase, is
an essential enzyme (Georgopapadakou and Walsh, 1996).
The accumulation of dimethyl-lanosterol and depletion of
ergosterol alters the composition of fungal cell membranes.
Dermatophytes are among the fungi most sensitive to
amorolfine, while yeasts are only moderately sensitive.
Molds vary in sensitivity, with Aspergillus spp. being
resistant and Alternaria spp. being highly sensitive (Polak,
1990).
Amino acids and peptides
Single amino acids as well as peptides and proteins have
been found to have antifungal activities. A large group of
cyclic peptides, lipopeptides and lipodepsipeptides
(containing one or several ester bonds) have been isolated
on their antifungal activity, and they act by several different
modes of action (Ziegelbauer et al., 1998).
Cyclic peptides
Of the antifungal cyclic peptides, aureobasidin has gained
much attention since its discovery (Ikai et al., 1991).
Aureobasidins are a group of cyclic depsipeptides with
antifungal activity produced by Aureobasidium pullulans
(Yoshikawa et al., 1993). Aureobasidins are composed of
eight amino acids and one hydroxy acid such as 2-hydroxy3-methylpentanoic acid (Hmp), and highly lipophilic and
showed inhibitory activity against the enzyme inositol
phosphoceramide (IPC) synthase, critical in fungal
sphingolipid biosynthesis. Sphingolipids, in turn, are vital
for the function of the cell membrane for fungi and humans
alike. The IPC enzyme, on the other hand, is lacking in
mammals, which means that all compounds selectively
inhibiting IPC are highly interesting for development of
antifungal drugs. The inhibition of this enzyme results in
the depletion of essential sphingolipids in the fungal cells.
Since all fungi have this enzyme, Aureobasidin A is
potentially a broad spectrum antifungal (Takesako et al.,
1991; 1993). Three of the new aureobasidins, S2b, S3 and
S4, which have hydroxylated Hmp as the hydroxy acid,
were highly active against Candida spp. and Cryptococcus
neoformans.
Academia Journal of Microbiology Research; Babatunde and Olusola.
Lipopeptides
Lipopeptides from Bacillus species, includes the surfactins,
iturins, and fengycins. The surfactins are powerful surfaceactive compounds, which show antibacterial activity but no
marked fungitoxicity (Ongena and Jacques, 2008). Iturins
are a crucial family of these cyclic lipopeptides and they are
derived only from B. subtilis and B. amyloliquefaciens and
exhibit strong antifungal activities against a wide variety of
yeasts and plant pathogenic fungi (Zhang et al., 2013). It has
been proposed that antimicrobial activity of iturins
depends predominantly on its capacity to increase
membrane permeabilization, which is being attributed to
aggregates formed by iturin molecules, iturin–phospholipid
complex or iturin–phospholipid–sterol complex (MagetDana and Peypoux, 1994). Microscopic observations (SEM
and TEM) revealed that growth inhibition of Rhizopus solani
as a response to Bacillomycin L was accompanied by
marked morphological and cytological changes, including
rough cell surface, condensation of the cytoplasms and
irregular architecture of organelles (Zhang et al., 2013).
Fengycins are the main lipopeptides having strong
antifungal activities (Ongena and Jacques, 2008). It has
antifungal activity against filamentous fungi. It inhibits
filamentous fungi but is ineffective against yeasts (Deleu et
al., 2008).
Lipodepsinonapeptides
Many strains of Pseudomonas syringae pv. syringae produce
one of four classes of small cyclic lipodepsinonapeptides:
syringomycins (Segre et al., 1989), syringotoxins (Ballio et
al., 1990; Harrison et al., 1991) syringostatins (Isogai et al.,
1990), and pseudomycins (Ballio et al., 1994). These
metabolites are phytotoxic and growth inhibitory against a
wide range of fungi (Sorensen et al., 1994). They are
thought to interact with the fungal cell membrane by pore
formation, which results in fatal electrolytic leakage
(Bender et al., 1999) and have been demonstrated to show
activity against Candida spp. and Aspergillus spp. All of
them have shown inhibitory activity against yeasts such as
Rhodotorula pilimanae and S. cerevisiae (Takemoto, 1992).
Syringomycins’ mechanism of action involves formation
of ion channels in the fungal plasma membrane employing
a novel sphingolipid-modulated channel formation
mechanism. Takemoto et al. (2002) found out that plasma
membrane pore formation is the mechanism of
syringomycin E action and that pore formation is
modulated by plasma membrane sphingolipids. Earlier,
Zhang and Takemoto (1989) found that Syringomycin
stimulated potassium efflux by yeast cells by stimulation of
one or more protein kinases of the host plasma membrane.
Also, plasma membrane-associated mannosyl-
027
inositolphospho-ceramides (sphingolipids) were shown to
promote growth inhibition ability of syringomycin E in
yeast (Bessonov et al., 2006). It is speculated that these
surface lipids participate in membrane pore forming
mechanisms involving physical interactions with
syringomycin E (Bessonov et al., 2006). Syringomycin Eglycolipid mixtures display fungicidal activities that are 2 to
5 -fold more potent than with syringomycin E alone (Kaulin
et al., 2005). Pseudomycin A is the predominant peptide
in a family of four including syringomycin, syringotoxin
and syringostatins,
and has showed
selective
phytotoxicity, as well as having impressive activity
against Candida albicans. Previous studies have shown
that pseudomycins are different from previously described
antimycotics from P. syringae (Segre et al., 1989; Bidwai et
al., 1986; Ballio et al., 1988; Gross et al., 1977; Isogai et al.,
1989). Pseudomycin A contains hydroxyaspartic acid,
aspartic acid, serine, arginine, lysine and diaminobutyric
acid and alongside other Cyclic lipodepsinonapeptides
(CLPs), target the fungal plasma membrane by altering
several membrane functions such as membrane potential,
protein phosphorylation, H1-ATPase activity, and cation
transport fluxes (Sorensen et al., 1996).
CONCLUSION
The ability to selectively target fungal cell components
instead of mammalian components given similarities is the
ultimate goal in the development of antifungal agents.
Various components of fungi cell membrane are targets for
the polyenes, azoles, allylamines, lipopeptides and statins
and they have shown remarkable activity against mycotic
infections. Ergosterol, a sterol unique to fungal cell has
been exploited in the development of antifungals and is the
major target of polyenes and azoles, while others target
specific enzymes important in membrane functions.
However, some of these agents though potent, cross react
with human cellular components e.g. sterols hence
resulting in toxicity to the host. This has limited the use of
antifungals to topical applications mostly. It is suggested
that in the further development of antifungal agents, it
should aim at synthesizing less toxic compounds with
corresponding high antifungal activity and reduced
possibility of resistance.
ACKNOWLEDGEMENT
We appreciate the Ekiti State University, Ado-Ekiti for the
library facilities, collation and typing of this document.
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