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Naoki Hosogaya,
Taiga Miyazaki,
Minoru Nagi,
Koichi Tanabe,
Asuka Minematsu,
Yohsuke Nagayoshi,
Shunsuke Yamauchi,
Shigeki Nakamura,
Yoshifumi Imamura,
Koichi Izumikawa,
Hiroshi Kakeya,
Katsunori Yanagihara,
Yoshitsugu Miyazaki,
Kiyotaka Kugiyama,
Shigeru Kohno
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ABSTRACT: The pathogenic fungus Candida glabrata is relatively resistant to azole antifungals, which target lanosterol 14α-demethylase (Erg11p) in the ergosterol biosynthesis pathway. Our study revealed that C. glabrata exhibits increased azole susceptibility under low-iron conditions. To investigate the molecular basis of this phenomenon, we generated a strain lacking the heme (iron protoporphyrin IX)-binding protein Dap1 in C. glabrata. The Δdap1 mutant displayed growth defects under iron-limited conditions, decreased azole tolerance, decreased production of ergosterol, and increased accumulation of 14α-methylated sterols lanosterol and squalene. All the Δdap1 phenotypes were complemented by wild-type DAP1, but not by DAP1(D91G) , in which a heme-binding site is mutated. Furthermore, azole tolerance of the Δdap1 mutant was rescued by exogenous ergosterol but not by iron supplementation alone. These results suggest that heme binding by Dap1 is crucial for Erg11 activity and ergosterol biosynthesis, thereby being required for azole tolerance. A Dap1-GFP fusion protein predominantly localized to vacuolar membranes and endosomes, and the Δdap1 cells exhibited aberrant vacuole morphologies, suggesting that Dap1 is also involved in the regulation of vacuole structures that could be important for iron storage. Our study demonstrates that Dap1 mediates a functional link between iron homeostasis and azole resistance in C. glabrata. © 2013 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.
FEMS Yeast Research 03/2013; · 2.40 Impact Factor
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Masato Tashiro,
Koichi Izumikawa,
Katsuji Hirano,
Shotaro Ide,
Tomo Mihara, Naoki Hosogaya,
Takahiro Takazono,
Yoshitomo Morinaga,
Shigeki Nakamura,
Shintaro Kurihara,
Yoshifumi Imamura,
Taiga Miyazaki,
Tomoya Nishino,
Misuzu Tsukamoto,
Hiroshi Kakeya,
Yoshihiro Yamamoto,
Katsunori Yanagihara,
Akira Yasuoka,
Takayoshi Tashiro,
Shigeru Kohno
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ABSTRACT: This is the first report of a detailed relationship between triazole treatment history and triazole MICs for 154 Aspergillus fumigatus clinical isolates. The duration of itraconazole dosage increased as the itraconazole MIC increased, and a positive correlation was observed (r = 0.5700, P < 0.0001). The number of itraconazole-naïve isolates dramatically decreased as the itraconazole MIC increased, particularly for MICs exceeding 2 μg/ml (0.5 μg/ml versus 2 μg/ml, P = 0.03). We also examined the relationship between cumulative itraconazole usage and the MICs of other azoles. A positive correlation existed between itraconazole dosage period and posaconazole MIC (r = 0.5237, P < 0.0001). The number of itraconazole-naïve isolates also decreased as the posaconazole MIC increased, particularly for MICs exceeding 0.5 μg/ml (0.25 μg/ml versus 0.5 μg/ml, P = 0.004). Conversely, the correlation coefficient obtained from the scattergram of itraconazole usage and voriconazole MICs was small (r = -0.2627, P = 0.001). Susceptibility to three triazole agents did not change as the duration of voriconazole exposure changed. In addition, we carried out detailed analysis, including microsatellite genotyping, for isolates obtained from patients infected with azole-resistant A. fumigatus. We confirmed the presence of acquired resistance to itraconazole and posaconazole due to a G54 substitution in the cyp51A gene for a patient with chronic pulmonary aspergillosis after oral itraconazole therapy. We should consider the possible appearance of azole-resistant A. fumigatus if itraconazole is used for extended periods.
Antimicrobial Agents and Chemotherapy 07/2012; 56(9):4870-5. · 4.84 Impact Factor
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Yoshihiro Yamamoto,
Koichi Izumikawa, Naoki Hosogaya,
Yoshitomo Morinaga,
Shigeki Nakamura,
Yoshifumi Imamura,
Taiga Miyazaki,
Noriho Sakamoto,
Yuji Ishimatu,
Hiroshi Kakeya,
Katsunori Yanagihara,
Akira Yasuoka,
Shigeru Kohno
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ABSTRACT: The prognosis of patients with chronic respiratory tract infections, especially diffuse panbronchiolitis, is remarkably improved by long-term administration of low-dose macrolides. However, in some cases, patients are refractory to macrolide treatment and show a low or no response; therefore, new treatment strategies are required. Here we present a patient refractory to either single low-dose clarithromycin or azithromycin but responded remarkably to the combination usage of both macrolides.
Internal Medicine 01/2012; 51(11):1383-6. · 0.94 Impact Factor
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Masato Tashiro,
Koichi Izumikawa,
Asuka Minematsu,
Katsuji Hirano,
Naoki Iwanaga,
Shotaro Ide,
Tomo Mihara, Naoki Hosogaya,
Takahiro Takazono,
Yoshitomo Morinaga, [......],
Yoshifumi Imamura,
Taiga Miyazaki,
Tomoya Nishino,
Misuzu Tsukamoto,
Hiroshi Kakeya,
Yoshihiro Yamamoto,
Katsunori Yanagihara,
Akira Yasuoka,
Takayoshi Tashiro,
Shigeru Kohno
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ABSTRACT: We investigated the triazole, amphotericin B, and micafungin susceptibilities of 196 A. fumigatus clinical isolates in Nagasaki, Japan. The percentages of non-wild-type (non-WT) isolates for which MICs of itraconazole, posaconazole, and voriconazole were above the ECV were 7.1%, 2.6%, and 4.1%, respectively. A G54 mutation in cyp51A was detected in 64.2% (9/14 isolates) and 100% (5/5 isolates) of non-WT isolates for itraconazole and posaconazole, respectively. Amphotericin B MICs of ≥2 μg/ml and micafungin minimum effective concentrations (MECs) of ≥16 μg/ml were recorded for two and one isolates, respectively.
Antimicrobial Agents and Chemotherapy 01/2012; 56(1):584-7. · 4.84 Impact Factor
