Effects of micafungin on the morphology of Aspergillus fumigatus

Nishiyama, Yayoi; Hasumi, Yayoi; Ueda, Katsura; Uchida, Katsuhisa; Yamaguchi, Hideyo

doi:10.1093/jmicro/dfh100

Cited by 43 publications

(30 citation statements)

References 32 publications

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“…A. fumigatus exposed to inhibitory concentrations of micafungin, an echinocandin, displayed hyphal burst (9, 19) and showed undulated membranes and deformed hyphae tips at sub-inhibitory concentrations (18). Candida albicans exposed to lethal dosage of echinocandins induce swelling and at sub-inhibitory dosage abnormal morphological changes were observed on the membrane (17, 20).…”

Section: Discussionmentioning

confidence: 99%

Occidiofungin, a Unique Antifungal Glycopeptide Produced by a Strain of Burkholderia contaminans

et al. 2009

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Bacterial strain Burkholderia contaminans MS14 was isolated from soil that suppressed brown patch disease of lawn grass. An antifungal compound was purified from the liquid culture of this bacterium. In this study, complete covalent structures of two purified closely related antifungal compounds were determined by the experiments of TOCSY, NOESY, ROESY, 13C HSQC 2D NMR, and ESI-MS and GC. The analysis of monoisotopic masses of the purified preparation indicated presence of two related compounds with masses determined to be 1199.543 Da and 1215.518 Da; the difference corresponds to the mass of an oxygen atom. GC analysis identified a xylose sugar attached to the antifungal compound. NMR experiments revealed that the compound is cyclic and composed of eight amino acids, two of which are β-hydroxy derivatives of Tyr and Asn, and one being a novel amino acid. The novel amino acid serves as the scaffold for the attachment of the xylose and a short acyl chain. The spectrum and concentration of antifungal activity was determined using a microtiter plate assay. The antifungal compound demonstrated potent antifungal activities against a broad panel of fungal plant and animal pathogens, as well as two Pythium spp. Microscopic observations showed that the antifungal compound disrupts normal membrane morphology. The cells fill with large inclusion bodies and the membrane becomes irregularly shaped and swollen following the exposure to sub-inhibitory concentrations of the antifungal compound. Our data support the identification of a novel fungicide and the compound has been named occidiofungin, meaning fungal killer.

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Section: Discussionmentioning

confidence: 99%

Occidiofungin, a Unique Antifungal Glycopeptide Produced by a Strain of Burkholderia contaminans

et al. 2009

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“…When most of the conidia began to germinate, sub-MIC (1/4 MIC) and MIC doses of ME1111 were added to the culture broth. After 4, 8, and 24 h of incubation, hyphal cells were collected by centrifugation and prepared for SEM and TEM samples as described previously (7,8).…”

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confidence: 99%

Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy

Nishiyama

Takahata

Abe

2017

Antimicrob Agents Chemother

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The effects of ME1111, a novel antifungal agent, on the hyphal morphology and ultrastructure of Trichophyton mentagrophytes were investigated by using scanning and transmission electron microscopy. Structural changes, such as pit formation and/or depression of the cell surface, and degeneration of intracellular organelles and plasmolysis were observed after treatment with ME1111. Our results suggest that the inhibition of energy production by ME1111 affects the integrity and function of cellular membranes, leading to fungal cell death. KEYWORDS antifungal agents, electron microscopy, mode of action, morphologyA new class of antifungal agent, ME1111 [2-(3, 5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol] is being developed as a topical agent for onychomycosis. It is highly active in vitro and in vivo against Trichophyton rubrum and Trichophyton mentagrophytes and shows excellent human nail permeability (1-4). A previous study on its mechanism of action revealed that the molecular target of ME1111 was succinate dehydrogenase (complex II) in the mitochondrial electron transport system (5). However, its effects on the morphology and ultrastructure of hyphal cells are poorly understood. Electron microscopy appeared to be the most suitable approach for a better understanding of the essential events involved in the antidermatophytic action of ME1111. In this study, we investigated the effect of ME1111 on the ultrastructure of T. mentagrophytes grown in a liquid medium by scanning electron microscopy (SEM) and transmission electron microscopy (TEM).T. mentagrophytes TIMM 2789 was grown in RPMI 1640 medium and Sabouraud dextrose broth (SDB) for study with SEM and TEM, respectively. The MIC of ME1111 against this strain was 0.5 g/ml in RPMI 1640 medium and 0.25 g/ml in SDB, based on the broth microdilution method (CLSI document M38-A2) (6). Conidia of T. menta-

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“…T. mentagrophytes (2 ϫ 10 4 microconidia/ml) was cultured in Sabouraud dextrose broth at 30°C for 24 h with shaking. After conidia germinated, efinaconazole was added to the medium, and cultures were incubated for an additional 24 h. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analysis of the hyphae was performed as described by Nishiyama et al (13), with minor modifications, using 2.5% glutaraldehyde for sample fixation and osmium tetroxide for SEM sample coating. Efinaconazole induced notable morphological and ultrastructural changes in hyphae ( Fig.…”

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Mechanism of Action of Efinaconazole, a Novel Triazole Antifungal Agent

Tatsumi

Nagashima

Shibanushi

et al. 2013

Antimicrob Agents Chemother

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The mechanism of action of efinaconazole, a new triazole antifungal, was investigated with Trichophyton mentagrophytes and Candida albicans. Efinaconazole dose-dependently decreased ergosterol production and accumulated 4,4-dimethylsterols and 4␣-methylsterols at concentrations below its MICs. Efinaconazole induced morphological and ultrastructural changes in T. mentagrophytes hyphae that became more prominent with increasing drug concentrations. In conclusion, the primary mechanism of action of efinaconazole is blockage of ergosterol biosynthesis, presumably through sterol 14␣-demethylase inhibition, leading to secondary degenerative changes. Ergosterol is an important structural component of fungal cell membranes, maintaining membrane fluidity and a permeability barrier, and is essential for fungal cell viability (1-3). Several classes of antifungal drugs target ergosterol biosynthesis. Among these, triazole antifungals (e.g., itraconazole) and imidazole antifungals (e.g., clotrimazole and miconazole) inhibit sterol 14␣-demethylase (14-DM) in the ergosterol biosynthesis pathway (4). The consequent ergosterol depletion affects cell membrane integrity and function and is believed to inhibit fungal cell growth and affect morphology.Efinaconazole, a novel triazole antifungal drug currently under development as a topical treatment for onychomycosis, has demonstrated efficacy in patients with toenail onychomycosis in two phase 3 clinical trials (5). Onychomycosis and other superficial mycoses are caused mainly by dermatophytes (e.g., Trichophyton rubrum and Trichophyton mentagrophytes) and yeast (e.g., Candida albicans). Efinaconazole possesses similar or higher antifungal activity against T. rubrum and T. mentagrophytes (MIC range, 0.00098 to 0.031 g/ml) and a broader spectrum of activity than those of currently marketed antifungals used in onychomycosis (6). We investigated the effects of efinaconazole on fungal ergosterol biosynthesis and dermatophyte hyphal morphology.In the present study, T. mentagrophytes strain SM-110 and C. albicans strain ATCC 10231 were used. The MICs of efinaconazole (Kaken Pharmaceutical), itraconazole, and clotrimazole (SigmaAldrich) were determined by the broth microdilution method using morpholinepropanesulfonic acid (MOPS)-buffered RPMI 1640, as described in CLSI documents M38-A2 (7) and M27-A3 (8), using visual endpoint readings of 80% growth inhibition at 4 days and 50% growth inhibition at 48 h, respectively. Efinaconazole was 4-fold more active than itraconazole against T. mentagrophytes SM-110 (MICs of 0.0039 and 0.016 g/ml, respectively). Similarly, efinaconazole was 8-fold more active than clotrimazole against C. albicans ATCC 10231 (MICs of 0.00098 and 0.0078 g/ml, respectively). The two strains showed typical susceptibilities to the antifungals tested, consistent with previous findings for these species (6, 9).Ergosterol biosynthesis assays were conducted by modifying the methods of Vanden Bossche et al. (10) and Ryder et al. (11). T. mentagrophytes (2 ϫ 10 8 microconidia/ml...

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Effects of micafungin on the morphology of Aspergillus fumigatus

Cited by 43 publications

References 32 publications

Occidiofungin, a Unique Antifungal Glycopeptide Produced by a Strain of Burkholderia contaminans

Occidiofungin, a Unique Antifungal Glycopeptide Produced by a Strain of Burkholderia contaminans

Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy

Mechanism of Action of Efinaconazole, a Novel Triazole Antifungal Agent

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