Fungal infections cause not only superficial diseases such as athlete’s
foot and onychomycoses, but also life-threatening diseases. Serious
deep-seated fungal infections caused by Candida spp., Aspergillus spp.
and Cryptococcus neoformans are a threat to human health. Incidences
of these systemic fungal infections have increased significantly over the
past few years. The major reasons for this dramatic increase are the
extensive use of broad-spectrum antibiotics and the growing number
of immunocompromised patients with acquired immunodeficiency
syndrome (AIDS), cancer and transplants.
In the mid 1900s, few compounds, such as polyenes (for example,
nystatin and amphotericin B) and flucytosine, were available for
antifungal chemotherapy. Although the development of azole drugs
started in the early 1970s, only a limited number of antifungal agents
were available for treatment of life-threatening fungal infections.
Moreover, the existing agents had disadvantages, such as the significant
nephrotoxicity of amphotericin B3 and the emergence of resistance
to the azoles.4 To overcome these defects, lipid formulations of
polyenes were developed to reduce toxicity, and new triazoles (for
example, voriconazole, ravuconazole and posaconazole) were developed
to improve the antifungal spectra or susceptibility to azoleresistant
isolates.5 Despite a number of therapeutic advancements,
there was a need to develop a new class of antifungal agents with novel
mechanisms of action.
The echinocandins were a new class of antifungal drugs developed
for the first time since azoles. The first launched echinocandin was
caspofungin acetate (Merck & Co. Inc. (Merck), Readington, NJ, USA),
followed by micafungin (Fujisawa Pharmaceutical Co., Ltd, now
Astellas Pharma Co., Ltd, Fujisawa, Japan) and anidulafungin (Vicuron
Pharmaceuticals Inc., now Pfizer Inc., New York, NY, USA), which was
originally developed by Eli Lilly and Company (Indianapolis, IN, USA)
(Lilly) as LY 303366 and subsequently licensed to Vicuron (formerly
Versicor) as VER-002. The approved echinocandins are synthetically
modified lipopeptides that originate from natural compounds produced
by filamentous fungi. The original anidulafungin, caspofungin
and micafungin compounds were echinocandin B from Aspergillus
nidulans var. echinulatus,6 pneumocandin B0 from Glarea lozoyensis7
and FR901379 from Coleophoma empetri,8 respectively.
Although natural echinocandins have potent antifungal activity
in vitro, their structures were chemically altered to improve their
absorption, distribution, metabolism and excretion characteristics.
Such operations were initiated by Lilly on echinocandin B to yield
cilofungin.9 This compound was subjected to Phase II clinical trials,
but was abandoned due to toxicity. Further modification of the
structure by converting the phenolic hydroxyl to a sodium phosphate
ester produced the more soluble prodrug LY307853, which resulted in
the active form, LY303366.10 Merck has produced MK-0991 using
pneumocandin B0 as the starting material.11 MK-0991 likewise possesses
increased water solubility. Other reviews on echinocandins or
individual antifungal agents have reported their usefulness in clinical
practice.12–16 This review describes the discovery and development of
micafungin, focusing on the chemical diversity of echinocandins.
DISCOVERY OF FR901379
The seed compounds of micafungin, FR901379 and two related
compounds (FR901381 and FR901382), were discovered at Fujisawa
Pharmaceutical Co., Ltd in 1989 from the screening of approximately
6000 microbial broth samples (Figure 1). These new compounds were
categorised as members of the echinocandin class of lipopeptides.
Echinocandin B, pneumocandin B0 and other echinocandin lipopeptides
are structurally characterized by a cyclic hexapeptide acylated
with a long side chain, and have an excellent anti-Candida activity
attributed to selective inhibition of 1,3-b-glucan synthesis, although
their intrinsic water insolubility is a major barrier for drug development.
17–19 However, FR901379 and related compounds showed both
high water solubility and a strong antifungal effect on Candida spp.20
The structural difference between FR901379 and the other echinocandins
is that FR901379 has a sulfate moiety in its molecule (Figure 1,
circled). This residue was speculated to be the basis for the high water
solubility of FR901379 (soluble in water even at a concentration of
50mgml 1, a concentration at which other compounds have low
solubility). To probe this hypothesis, FR901379 was digested with aryl
sulfatase from Aerobacter aerogenes (Table 1), after which the water
solubility of the desulfated molecule (FR133302) was decreased to
1mgml 1, even though the inhibitory activity on 1,3-b-glucan
synthase did not decrease markedly.21 This result indicated that the
excellent water solubility of FR901379 was attributed to the sulfate
moiety in its structure.
The IC50 value of FR901379 on 1,3-b-glucan synthase is
0.7 mgml1, which is superior to that of echinocandin B (Table 1).
The in vitro antifungal activity of FR901379 and related compounds
against both Candida albicans and A. fumigatus indicates a higher
potency than that of aculeacin A (Table 2); however, it is only weakly
active against A. fumigatus. None of these compounds show antifungal
activity against C. neoformans. Table 3 shows the therapeutic effect of
FR901379 in a murine C. albicans infection model in which drugs
were administered s.c. for four consecutive days. FR901379 and related
compounds significantly prolonged the survival of infected mice.
FR901379 was the most potent compound, with an ED50 value of
2.7mg kg1 14 days after the infection. This value was almost
comparable to that of fluconazole. In spite of its potent antifungal
activity and its good water solubility, FR901379 could not be developed
further because of class-specific reticulocyte lysis at low concentrations
(Table 4), although the lytic activity of FR901379 was
weaker than that of amphotericin B.
The producer strain of FR901379, identified as C. empetri F-11899,
was originally isolated from a soil sample collected at Iwaki City,
Fukushima Prefecture, Japan. Its morphological characteristics were
determined on the basis of cultures on sterilized azalea leaf affixed to a
Miura’s LCA plate, because the strain produced conidial structures on
the leaf segment alone.
foot and onychomycoses, but also life-threatening diseases. Serious
deep-seated fungal infections caused by Candida spp., Aspergillus spp.
and Cryptococcus neoformans are a threat to human health. Incidences
of these systemic fungal infections have increased significantly over the
past few years. The major reasons for this dramatic increase are the
extensive use of broad-spectrum antibiotics and the growing number
of immunocompromised patients with acquired immunodeficiency
syndrome (AIDS), cancer and transplants.
In the mid 1900s, few compounds, such as polyenes (for example,
nystatin and amphotericin B) and flucytosine, were available for
antifungal chemotherapy. Although the development of azole drugs
started in the early 1970s, only a limited number of antifungal agents
were available for treatment of life-threatening fungal infections.
Moreover, the existing agents had disadvantages, such as the significant
nephrotoxicity of amphotericin B3 and the emergence of resistance
to the azoles.4 To overcome these defects, lipid formulations of
polyenes were developed to reduce toxicity, and new triazoles (for
example, voriconazole, ravuconazole and posaconazole) were developed
to improve the antifungal spectra or susceptibility to azoleresistant
isolates.5 Despite a number of therapeutic advancements,
there was a need to develop a new class of antifungal agents with novel
mechanisms of action.
The echinocandins were a new class of antifungal drugs developed
for the first time since azoles. The first launched echinocandin was
caspofungin acetate (Merck & Co. Inc. (Merck), Readington, NJ, USA),
followed by micafungin (Fujisawa Pharmaceutical Co., Ltd, now
Astellas Pharma Co., Ltd, Fujisawa, Japan) and anidulafungin (Vicuron
Pharmaceuticals Inc., now Pfizer Inc., New York, NY, USA), which was
originally developed by Eli Lilly and Company (Indianapolis, IN, USA)
(Lilly) as LY 303366 and subsequently licensed to Vicuron (formerly
Versicor) as VER-002. The approved echinocandins are synthetically
modified lipopeptides that originate from natural compounds produced
by filamentous fungi. The original anidulafungin, caspofungin
and micafungin compounds were echinocandin B from Aspergillus
nidulans var. echinulatus,6 pneumocandin B0 from Glarea lozoyensis7
and FR901379 from Coleophoma empetri,8 respectively.
Although natural echinocandins have potent antifungal activity
in vitro, their structures were chemically altered to improve their
absorption, distribution, metabolism and excretion characteristics.
Such operations were initiated by Lilly on echinocandin B to yield
cilofungin.9 This compound was subjected to Phase II clinical trials,
but was abandoned due to toxicity. Further modification of the
structure by converting the phenolic hydroxyl to a sodium phosphate
ester produced the more soluble prodrug LY307853, which resulted in
the active form, LY303366.10 Merck has produced MK-0991 using
pneumocandin B0 as the starting material.11 MK-0991 likewise possesses
increased water solubility. Other reviews on echinocandins or
individual antifungal agents have reported their usefulness in clinical
practice.12–16 This review describes the discovery and development of
micafungin, focusing on the chemical diversity of echinocandins.
DISCOVERY OF FR901379
The seed compounds of micafungin, FR901379 and two related
compounds (FR901381 and FR901382), were discovered at Fujisawa
Pharmaceutical Co., Ltd in 1989 from the screening of approximately
6000 microbial broth samples (Figure 1). These new compounds were
categorised as members of the echinocandin class of lipopeptides.
Echinocandin B, pneumocandin B0 and other echinocandin lipopeptides
are structurally characterized by a cyclic hexapeptide acylated
with a long side chain, and have an excellent anti-Candida activity
attributed to selective inhibition of 1,3-b-glucan synthesis, although
their intrinsic water insolubility is a major barrier for drug development.
17–19 However, FR901379 and related compounds showed both
high water solubility and a strong antifungal effect on Candida spp.20
The structural difference between FR901379 and the other echinocandins
is that FR901379 has a sulfate moiety in its molecule (Figure 1,
circled). This residue was speculated to be the basis for the high water
solubility of FR901379 (soluble in water even at a concentration of
50mgml 1, a concentration at which other compounds have low
solubility). To probe this hypothesis, FR901379 was digested with aryl
sulfatase from Aerobacter aerogenes (Table 1), after which the water
solubility of the desulfated molecule (FR133302) was decreased to
1mgml 1, even though the inhibitory activity on 1,3-b-glucan
synthase did not decrease markedly.21 This result indicated that the
excellent water solubility of FR901379 was attributed to the sulfate
moiety in its structure.
The IC50 value of FR901379 on 1,3-b-glucan synthase is
0.7 mgml1, which is superior to that of echinocandin B (Table 1).
The in vitro antifungal activity of FR901379 and related compounds
against both Candida albicans and A. fumigatus indicates a higher
potency than that of aculeacin A (Table 2); however, it is only weakly
active against A. fumigatus. None of these compounds show antifungal
activity against C. neoformans. Table 3 shows the therapeutic effect of
FR901379 in a murine C. albicans infection model in which drugs
were administered s.c. for four consecutive days. FR901379 and related
compounds significantly prolonged the survival of infected mice.
FR901379 was the most potent compound, with an ED50 value of
2.7mg kg1 14 days after the infection. This value was almost
comparable to that of fluconazole. In spite of its potent antifungal
activity and its good water solubility, FR901379 could not be developed
further because of class-specific reticulocyte lysis at low concentrations
(Table 4), although the lytic activity of FR901379 was
weaker than that of amphotericin B.
The producer strain of FR901379, identified as C. empetri F-11899,
was originally isolated from a soil sample collected at Iwaki City,
Fukushima Prefecture, Japan. Its morphological characteristics were
determined on the basis of cultures on sterilized azalea leaf affixed to a
Miura’s LCA plate, because the strain produced conidial structures on
the leaf segment alone.
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