Antifungal agent

Abstract

To provide an antifungal agent against fungal pathogens that cause candidiasis, and a pharmaceutical composition for treating candidiasis comprising the antifungal agent.SOLUTION: Provided is an antifungal agent against fungal pathogens that cause candidiasis, the antifungal agent containing N-[(2E)-2-[(4-nitrophenyl)hydrazinylidene]propyl]acetamide or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to an antifungal agent. [Background technology]

[0002] Pathogenic Candida fungi are normally present on the epidermis, intestinal mucosa, vagina, etc., but can cause serious deep-seated (visceral) infections in patients with risk factors such as long-term administration of antibiotics, steroids, anticancer drugs, or immunosuppressants, or patients with organ transplants, AIDS, severe diabetes, or indwelling catheters. In Japan, Candida is the fourth most common cause of bloodstream infections (including bacterial infections) (7-8%), and is a serious opportunistic infection with a mortality rate of 20-50%. The first choice for treatment is antifungal drugs (see, for example, Patent Document 1). Conventional antifungal agents against the causative bacteria of candidiasis are classified into four groups: fluoropyrimidines, echinocandins, polyenes, and azoles. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2014-028780 A Summary of the Invention [Problem to be solved by the invention]

[0004] The emergence of resistant bacteria has become a problem due to the overuse of the four existing systems. There is a need for the development of new systems of drugs that do not belong to the four existing systems. There is also a need for the development of antifungal drugs with fewer side effects. An objective of the present invention is to provide an antifungal agent against the causative fungus of candidiasis and a pharmaceutical composition for treating candidiasis containing the antifungal agent. [Means for solving the problem]

[0005] The present invention relates to the following <1> ~ <5> Regarding. <1> An antifungal agent against a causative fungus of candidiasis, comprising as an active ingredient a compound represented by the following formula (1) or a pharma- ceutically acceptable salt thereof, or a solvate thereof:

[0006] [ka]

[0007] <2> The causative bacterium of candidiasis is selected from the group consisting of Candida tropcalis, Candida albicans, Candida glabrata (also known as Nakaseomyces glabratus), Candida krusei (also known as Pichia kudriavzevii), Candida auris, and Candida parapsilosis. <1> The antifungal agent according to claim 1. <3> The causative bacterium of candidiasis is selected from the group consisting of Candida albicans, Candida glabrata (also known as Nakaseomyces glabratus), Candida krusei (also known as Pichia kudriavzevii), Candida auris, and Candida parapsilosis. <1> The antifungal agent according to claim 1. <4> The causative agent of candidiasis is the causative agent of invasive candidiasis. <1> ~ <3> 13. The antifungal agent according to claim 12, <5> <1> ~ <4> 13. A pharmaceutical composition for treating candidiasis, comprising the antifungal agent according to any one of claims 1 to 12. Effect of the Invention

[0008] According to the present invention, there are provided an antifungal agent against the causative fungus of candidiasis and a pharmaceutical composition for treating candidiasis containing the antifungal agent. [Brief description of the drawings]

[0009] [Figure 1]FIG. 1 is a DNA alignment showing the human ERG25 base sequence (SC4MOL) and human ERG25 converted to S. cerevisiae codons (hERG25). [Figure 2-1] FIG. 2-1 is a diagram showing the complementation of human SC4MOL and Candida glabrata ERG25 in S. cerevisiae (growth curves, and the results of t-test and one-way analysis of variance). [Figure 2-2] FIG. 2-2 is a diagram showing the complementation of human SC4MOL and Candida glabrata ERG25 in S. cerevisiae (spot assay). [Diagram 3] FIG. 3 shows the results of evaluating the proliferation inhibition by the compound represented by formula (1) targeting Erg25p. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] [Antifungal agent against the causative agent of candidiasis] The antifungal agent for the causative agent of candidiasis (pathogenic Candida) of this embodiment contains, as an active ingredient, a compound represented by the following formula (1) or a pharma- ceutically acceptable salt thereof, or a solvate thereof (hereinafter also referred to as antifungal agent (1)).

[0011] [ka]

[0012] The compound represented by formula (1) is N-[(2E)-2-[(4-nitrophenyl)hydrazinylidene]propyl]acetamide, and can be produced, for example, according to the method described in JP-A-55-120504.

[0013] Other pharma- ceutically acceptable salts of the compound represented by the above formula (1) include acid addition salts and base addition salts. The acid addition salt may be either an inorganic acid salt or an organic acid salt. Examples of inorganic acid salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; sulfates, nitrates, phosphates, perchlorates, and carbonates. Examples of organic acid salts include carboxylates such as citrate, oxalate, acetate, formate, propionate, benzoate, trichloroacetate, trifluoroacetate, hydroxyacetate, lactate, mandelate, butyrate, maleate, tartrate, and malate; amino acid salts such as arginate, aspartate, and glutamate; methanesulfonate, benzenesulfonate, and paratoluenesulfonate. The base addition salt may be either an inorganic base salt or an organic base salt. Examples of the inorganic base salt include sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt. Examples of the organic base salt include triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt.

[0014] The antifungal agent of the present embodiment may contain a solvate of the compound represented by the above formula (1) or a pharma- ceutically acceptable salt thereof as an active ingredient. The solvate is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include hydrates and ethanol solvates.

[0015] Examples of causative bacteria of candidiasis that are targeted by the antifungal agent (1) of this embodiment include Candida auris, Candida haemulonii, Candida pseudohaemulonii, Candida doubushaemulonii, Candida lusitaniae, Candida guilliermondii, Candida albicans, Candida dubliniensis, Candida tropicalis, Candida orthopsilosis, Candida parapsilosis, Candida krusei, and Candida glabrata. The causative agent of candidiasis is preferably a causative agent of invasive candidiasis. Among these, it is preferably selected from the group consisting of Candida tropcalis, Candida albicans, Candida glabrata (also known as Nakaseomyces glabratus), Candida krusei (also known as Pichia kudriavzevii), Candida auris, and Candida parapsilosis, more preferably selected from the group consisting of Candida albicans, Candida glabrata (also known as Nakaseomyces glabratus), Candida krusei (also known as Pichia kudriavzevii), Candida auris, and Candida parapsilosis, and even more preferably selected from the group consisting of Candida auris and Candida parapsilosis.

[0016] The antifungal agent (1) has an excellent antibacterial effect against the causative bacteria of candidiasis, and therefore, the antifungal agent (1) can be suitably used, for example, as an active ingredient of a pharmaceutical composition for treating candidiasis, which will be described later. They can also be suitably used for use in therapy, for use in the prevention or treatment of infectious diseases, and for the manufacture of medicaments for the prevention or treatment of infectious diseases.

[0017] As shown in the Examples, the antifungal agent (1) was found to have an antifungal effect against the causative bacteria of candidiasis by screening for sterol-C4-methyl monooxygenase (Erg25p) involved in the ergosterol synthesis pathway as a target. The Candida glabrata ERG25 gene or its human orthologue, human SC4MOL gene, was knocked into the ERG25 gene-deficient budding yeast S. cerevisiae, and the toxicity (IC) of the strains against a wild-type strain (BY4741), a Candida glabrata ERG25 knock-in strain (Sc(CgERG25)), and a human ERG25 (human SC4MOL genes) knock-in strain (Sc(hERG25)) was measured. 50 ) and IC against Sc(CgERG25) 50 IC against Sc(hERG25) 50 It has been confirmed that the Therefore, the antifungal agent (1) is expected to have excellent antifungal effects against the causative bacteria of candidiasis, and to have few side effects on subjects of treatment such as humans.

[0018] [Pharmaceutical composition for treating candidiasis] The pharmaceutical composition for treating candidiasis of this embodiment (hereinafter also simply referred to as "pharmaceutical composition") contains the antifungal agent of this embodiment, and further contains other ingredients as necessary. The total content of the antifungal agent (1) in the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose. The pharmaceutical composition may consist of only the antifungal agent (1).

[0019] <Other ingredients> The other components are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately selected depending on the purpose. The content of the other components in the pharmaceutical composition is not particularly limited, and can be appropriately selected depending on the purpose within a range that does not impair the effect of the antifungal agent (1).

[0020] <Dosage Form> The formulation form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the administration route. Examples of the formulation include injectables mainly used for intravenous injection, intramuscular injection, etc.; oral preparations such as capsules, tablets, granules, powders, pills, fine granules, syrups, and troches; external preparations for parenteral administration such as ointments, eye drops, ear drops, nasal drops, eye ointments, skin and mucous membrane absorbents, dermatological preparations, inhalants, and suppositories; other dry powders; and atomized aerosol formulations. The preparations can be produced by a conventional method using additives such as excipients, bulking agents, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, antiseptics, flavoring agents, soothing agents, and stabilizers.

[0021] Specific examples of the additives for injections, eye drops, ear drops, and nasal drops include dissolving agents or dissolving aids capable of constituting an aqueous or ready-to-use dissolving formulation (distilled water for injection, physiological saline, ethanol, glycerin, propylene glycol, corn oil, sesame oil, etc.), pH adjusters (inorganic acid addition salts such as trisodium orthophosphate and sodium bicarbonate; organic acid salts such as sodium citrate; organic basic salts such as L-lysine and L-arginine; etc.), isotonicity agents (sodium chloride, glucose, glycerin, etc.), buffers (sodium chloride, benzalkonium chloride, sodium citrate, etc.), surfactants (sorbitan monooleate, polysorbate 80, etc.), dispersing agents (D-mannitol, etc.), and stabilizers (antioxidants such as ascorbic acid, sodium sulfite, sodium pyrosulfite, etc.; chelating agents such as citric acid, tartaric acid, etc.). For example, eye ointments, skin and mucous membrane absorbents, and dermatological preparations include formulation components suitable for ointments, creams, and patches (white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.). For example, liquid inhalants include pH adjusters (sodium citrate, sodium hydroxide, etc.), isotonicity agents (sodium chloride, benzalkonium chloride, sodium citrate, etc.), and buffers (sodium chloride, benzalkonium chloride, sodium citrate, etc.). For example, powder inhalants include lactose as a carrier. For example, for oral administration agents and suppositories, examples of the ingredients include excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (shellac, hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), plasticizers (glycerin, polyethylene glycol, etc.), substrates (cocoa butter, polyethylene glycol, hard fat, etc.), etc.

[0022] <Administration> The administration route, dosage, administration time, and administration subject of the pharmaceutical composition are not particularly limited and can be appropriately selected depending on the purpose. The administration route is not particularly limited, and may be oral or parenteral depending on the site of infection, the properties of the individual to be administered, etc. Examples of parenteral administration include intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration, topical administration to the eye, and pulmonary administration. The dosage is not particularly limited, and can be appropriately selected in consideration of various factors such as the method of use, the type of causative fungus of candidiasis, the age, sex, weight, constitution, and severity of the disease of the individual to be administered, the presence or absence of administration of medicines or drugs containing other ingredients as active ingredients, etc. For example, when orally administered to humans, the dosage can be within the range of 0.1 mg / kg to 1,000 mg / kg per day per adult, and when intravenously administered, the dosage can be within the range of 0.01 mg / kg to 100 mg / kg per day. The administration timing, administration interval, and administration period are not particularly limited and can be appropriately selected depending on the purpose. The animal species to be administered is not particularly limited and can be appropriately selected depending on the purpose. Examples include humans, monkeys, pigs, cows, sheep, goats, dogs, cats, mice, rats, and birds, and among these, humans are preferred.

[0023] -Applications- The candidiasis to be treated by the pharmaceutical composition is not particularly limited, and examples include Candida meningitis, Candida endophthalmitis, oral candidiasis, esophageal candidiasis, cutaneous candidiasis, respiratory candidiasis, Candida endocarditis, hepatosplenic candidiasis, and digestive candidiasis.

[0024] The pharmaceutical composition may be used alone or in combination with a medicine containing another ingredient as an active ingredient.The pharmaceutical composition may be used in a state where it is incorporated in a medicine containing another ingredient as an active ingredient.

[0025] The pharmaceutical composition contains the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof, or a solvate thereof, and can prevent or treat candidiasis by administering the pharmaceutical composition to an individual. Thus, the present embodiment also relates to a method for preventing or treating candidiasis, comprising administering the pharmaceutical composition to an individual. In this embodiment, prevention of candidiasis refers to suppressing infection of an individual with Candida fungus, suppressing the proliferation of Candida fungus before symptoms appear, suppressing the occurrence of symptoms after infection with Candida fungus, suppressing recurrence after treatment, etc. In addition, in this embodiment, treatment of candidiasis refers to alleviating symptoms or preventing the worsening of symptoms, suppressing the proliferation of Candida fungus after symptoms have appeared, and the like.

[0026] The compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof, or a solvate thereof can also be used as a standard substance in screening for antifungal agents against the causative fungus of candidiasis. 50、 In a test using susceptibility such as MIC as an index, a test substance having superior performance to the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof, or a solvate thereof can be selected as a candidate antifungal agent. EXAMPLES

[0027] The present invention will be specifically described below with reference to examples and test examples of the present invention, but the present invention is not limited to these examples and test examples.

[0028] The fungal strains used in this example are shown in Table 1 below. In the table, Parental strain indicates the parent strain, Genotype indicates the genotype, and Resource indicates the source of acquisition.

[0029] [Table 1]

[0030] In addition, Escherichia coli ME9806 (iVEC3) (National BioResource Project (NBRP)) was used as a cloning host for plasmid construction. E. coli strains were grown in LB medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 50 μg / mL ampicillin. YEp352-GAPII plasmid containing the TDH3 promoter and URA3 gene, and YEp351-GAPII plasmid containing the TDH3 promoter and LEU2 gene were used for recombinant protein expression. All yeast strains were grown in YPD medium (1% Bacto Yeast Extract (Gibco), 2% HIPOLIPEPTON (Nihon Seiyaku), 2% glucose) or SD medium (0.17% Yeast Nitrogen Base without amino acids and ammonium sulfate, 5% ammonium sulfate (Fujifilm Wako Pure Chemical), 2% glucose, and appropriate amino acids). Solid medium was supplemented with 2% agar (Fujifilm Wako Pure Chemical). The compound represented by formula (1) (N-[(2E)-2-[(4-nitrophenyl)hydrazinylidene]propyl]acetamide) was obtained from ChemDiv.

[0031] <Construction of Sc(hERG25) and Sc(CgERG25)> The gene encoding human SC4MOL (hERG25), which was optimized for expression in S. cerevisiae, was custom-ordered from Eurofins Genomics (Figure 1). Figure 1 is a DNA alignment of the human ERG25 nucleotide sequence (SC4MOL) and the human ERG25 converted to S. cerevisiae codons (hERG25). In Figure 1, the homologous sequences are indicated by asterisks (*). A DNA fragment containing hERG25 was synthesized by PCR (polymerase chain reaction) using primers hERG25-F1 and hERG25-R1 (all primers are listed in Table 2). Also, the region having the TDH3 promoter and URA3 gene was amplified using the YEp352-GAPII plasmid as a template. The above DNA fragment was introduced into the fragment amplified from YEp352-GAPII by in vivo cloning using the E. coli strain ME9806 (iVEC3) (see Nozaki, S. et. al., “Exonuclease III (XthA) Enforces In Vivo DNA Cloning of Escherichia coli To Create Cohesive Ends”, J. Bacteriol. 2019, 201). The obtained plasmid YEp352-GAPII-hERG25 was used to transform Sc(ERG25Δ / ERG25) cells (see Gietz, R.D. and Schiestl, R.H. 1995. Transforming yeast with DNA. Meths Mol Cell Biol 5: 255-269). Next, the URA+ transformants were inoculated onto a solid sporulation medium containing 1% potassium acetate and 2% agar at 28 °C for 2 days. Sporulation was confirmed by microscopy, and the spores were plated on YPD agar medium. The obtained haploid strains were subcultured using the replica plating method in three types of media: YPD, SD-URA, and SD+G418 (200 μg / mL). The strains that grew in all three media were named Sc(hERG25). A DNA fragment encoding CgERG25 was amplified using primers CgERG25-F1 and CgERG25-R1 and genomic DNA of C. glabrata (Table 2) as a template. A region containing the TDH3 promoter and LEU2 was amplified using primers YEp352-GAPII-F3 and YEp352-GAPII-R3, using the YEp351-GAPII plasmid as a template. A DNA fragment encoding CgERG25 was introduced into the fragment amplified from YEp351-GAPII by in vivo cloning using E. coli strain ME9806 (iVEC3). The resulting plasmid YEp351-GAPII-CgERG25 was transformed into Sc(hERG25) cells and selected on SD medium without uracil and leucine. The transformants were selected on SD plates containing 5-fluoroorotic acid (5-FOA) without leucine, and Sc(CgERG25) was obtained.

[0032] [Table 2]

[0033] Liquid growth assay Strains were inoculated into YPD medium and grown to saturation overnight. Growth assays were performed in 96-well flat-bottom plates in 100 μL of SD medium with or without 20 mg / L uracil or 20 mg / L leucine. Starting cell concentrations were either 50,000 or 1,000 cells, but were standardized within individual experiments. Growth rates were monitored using an Infinite M200PRO (TECAN) at 28°C for at least 288 cycles, with optical density at 600 nm (OD ) approximately every 10 min. 600 The optical density at 100 nm was measured. Drugs were dissolved in dimethyl sulfoxide (DMSO) and dispensed onto the plate. The growth rate of each strain was calculated as follows: (1) The baseline of the growth curve was set to zero by averaging the first 10 OD measurements and subtracting them from all OD measurements of the corresponding curve. (2) The area under the curve (AUC) was calculated as the sum of all OD measurements. "Relative growth" was calculated based on the following formula with reference to Schlecht, U. et. al., “Multiplex Assay for Condition-Dependent Changes in Protein-Protein Interactions.”, Proc. Natl. Acad. Sci. 2012, 109, 9213-9218, doi:10.1073 / pnas.1204952109. (AUC condition - AUC control ) / AUC control Here, AUCcontrol represents the growth rate of the reference condition assayed on the same microtiter plate.

[0034] <Spotting assay> Next, the strain was inoculated on solid SD medium containing 2% agar with or without 20 mg / L uracil or 20 mg / L leucine at 28 °C for 2 days. Two to three single colonies were suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.). Using a cell counter (manufactured by Waterson Co., Ltd., Japan), it was adjusted to 2×10 6 cells / mL, serially diluted 1:10, and spotted (5 μL) onto solid SD medium containing 2% agar using an epMotion R 96 (manufactured by Eppendorf). After incubating at 28 °C for 48 hours, a photograph of cell growth was taken. The assay was repeated 3 times.

[0035] <Determination of MIC> The determination of MIC was basically performed according to the CLSI-M27A guideline. Various strains were streaked on YPD agar medium and incubated at 28 °C for 1 or 2 days until colonies appeared. Five of the emerged 1-mm colonies were picked up and suspended in a tube containing 1 mL of sterile physiological saline (0.9%). The resulting suspension was vortexed for 1 minute. The cell count was measured with a hemocytometer, and the final cell count was adjusted to 3×10 in RPMI MOPS medium3 The concentration of the cells was adjusted to 100 μg / mL. The drugs used were dissolved in DMSO and adjusted to a concentration of 10 μg / mL. The final concentration of the bacterial solution was adjusted, and the cell suspension was dispensed into a 96-well microplate in 100 μL portions using a multichannel pipette. Drugs were added by mixing 20 μL in the first row, and further diluted in 100 μL portions at two-fold intervals (the highest drug concentration was 1 / 10 of the added concentration). Incubation was started at 28°C for 48 hours. The cells were then incubated in the microplate at 28°C for 48 hours. The drug concentration in the well was defined as 0 (clear) and the MIC after visual comparison with the growth of the growth control.

[0036] [Complementation of hERG25 and CgERG25 in Saccharomyces cerevisiae] We obtained strains expressing ERG25 from Candida glabrata and its human orthologue SC4MOL in ERG25-deficient budding yeast strains. Since ERG25 is an essential gene in budding yeast, strains lacking ERG25 cannot grow. In addition, insufficient function during the expression process is reflected in the growth state, i.e., the turbidity of liquid culture and colony formation on agar plates. The growth curves of Sc(hERG25), Sc(CgERG25), and BY4741 showed almost the same slope, and t test and one-way ANOVA showed no significant differences (Figure 2-1). Furthermore, spot assays did not show different colony formation properties between them (Figure 2-2). These results indicate that hERG25 and CgERG25 are complementary in S. cerevisiae.

[0037] The growth inhibitory activity of the compound represented by formula (1) against BY4741, Sc (hERG25), and Sc (CgERG25) was compared (Figure 3). The IC 50 The IC of Sc(hERG25) was 13 μM and 3 μM, respectively. 50was >32 μM (Table 3). Therefore, the compound represented by formula (1) was found to inhibit proliferation of Sc(CgERG25), but not Sc(hERG25).

[0038] [Table 3]

[0039] In order to evaluate the antifungal activity spectrum against Candida species of the compound represented by formula (1) in which the growth inhibitory activity against Sc (CgERG25) was confirmed, the antifungal activity against Candida albicans SC5314, Candida glabrata CBS 138, Candida auris CBS 10913, Candida tropcalis CBS 94, Candida parapsilosis CBS 604 and Candida krusei CBS 573 was evaluated by a method in accordance with CLSI (Clinical and Laboratory Standards Institute)-M27A. The results are shown in Table 4 below.

[0040] [Table 4]

[0041] As shown in Table 4, the MIC was 16 μM against Candida tropcalis, showing relatively weak antifungal activity. On the other hand, the MIC was 2 μM or less against Candida albicans, Candida glabrata, Candida krusei, Candida auris, and Candida parapsilosis, showing strong antifungal activity. In particular, the MIC was 1 μM or less against Candida auris and Candida parapsilosis, showing particularly strong antifungal activity. [Industrial Applicability]

[0042] The antifungal agent of the present embodiment is useful as an antifungal agent against the causative bacteria of candidiasis, and while it exhibits strong growth inhibitory activity against yeast expressing ERG25 of Candida glabrata, it exhibits weak growth inhibitory activity against yeast expressing SC4MOL, which is its human ortholog (homologous gene), and is therefore expected to be an excellent antifungal agent against the causative bacteria of candidiasis with low side effects in humans.

Claims

1. An antifungal agent against a causative fungus of candidiasis, comprising as an active ingredient a compound represented by the following formula (1) or a pharma- ceutically acceptable salt thereof, or a solvate thereof: 【Chemistry 1】

2. The antifungal agent according to claim 1, wherein the causative fungus of candidiasis is selected from the group consisting of Candida tropcalis, Candida albicans, Candida glabrata (also known as Nakaseomyces glabratus), Candida krusei (also known as Pichia kudriavzevii), Candida auris, and Candida parapsilosis.

3. The antifungal agent according to claim 1, wherein the causative fungus of candidiasis is selected from the group consisting of Candida albicans, Candida glabrata (also known as Nakaseomyces glabratus), Candida krusei (also known as Pichia kudriavzevii), Candida auris, and Candida parapsilosis.

4. The antifungal agent according to claim 1, wherein the causative fungus of candidiasis is a causative fungus of invasive candidiasis.

5. A pharmaceutical composition for treating candidiasis, comprising the antifungal agent according to any one of claims 1 to 4.

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