A genome-wide screening of potential target genes to enhance the antifungal activity of micafungin in Schizosaccharomyces pombe.
A genome-wide screening of potential target genes to enhance the antifungal activity of micafungin in Schizosaccharomyces pombe.
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DOI：
10.1371/journal.pone.0065904
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kuno T
中科院分区：
文献类型：
--
作者：
Zhou X;Ma Y;Fang Y;gerile W;Jaiseng W;Yamada Y;Kuno T
米卡芬净是1，3-β-D-葡聚糖合成酶的不可逆抑制剂，干扰真菌细胞壁的合成。临床上，米卡芬净已被证明对侵袭性念珠菌病和侵袭性曲霉菌病有效。然而，考虑到其抗真菌谱相对有限，危重患者应考虑米卡芬净与其他药物的联合治疗。为了确定增强米卡芬净作用的融合药物组合的潜在治疗靶点，我们使用模型酵母裂殖酵母突变体库进行了全基因组范围的米卡芬净敏感性改变筛查。我们确认文库中的159株缺失菌株是米卡芬敏感的，并将其分为多种功能类别，包括细胞壁生物合成、基因表达和染色质重塑、膜转运、信号转导、泛素化、麦角甾醇生物合成过程以及其他各种已知或未知功能。另一方面，我们还考察了抗真菌药物两性霉素B、氟康唑和免疫抑制药物FK506与米卡芬净合用时的生长抑制活性。我们发现两性霉素B与米卡芬净合用对野生型细胞的抑制作用比单用米卡芬净更强，而氟康唑与米卡芬净合用对野生型细胞的抑制作用不明显。免疫抑制药FK506与米卡芬净对野生型细胞的生长有协同抑制作用，而对细胞壁完整性丝裂原活化蛋白激酶1的缺失突变体Δpmk1细胞，米卡芬净的抑制作用减弱。总之，我们的发现为治疗真菌感染的新的潜在药物组合提供了有用的信息。
Micafungin is a non-reversible inhibitor of 1, 3-β-D-glucan synthase and interferes with fungal cell wall synthesis. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. However, considering its relatively restricted antifungal spectrum, combination therapy with micafungin plus other agents should be considered in critically ill patients. To identify potential therapeutic targets for syncretic drug combinations that potentiate micafungin action, we carried out a genome-wide screen for altered sensitivity to micafungin by using the model yeast Schizosaccharomyces pombe mutant library. We confirmed that 159 deletion strains in the library are micafungin sensitive and classified them into various functional categories, including cell wall biosynthesis, gene expression and chromatin remodeling, membrane trafficking, signaling transduction, ubiquitination, ergosterol biosynthetic process and a variety of other known functions or still unknown functions. On the other hand, we also investigated the growth inhibitory activities of some well-known drugs in combination with micafungin including antifungal drug amphotericin B, fluconazole and immunosuppressive drug FK506. We found that amphotericin B in combination with micafungin showed a more potent inhibitory activity against wild-type cells than that of micafungin alone, whereas fluconazole in combination with micafungin did not. Also, the immunosuppressive drug FK506 showed synergistic inhibitory effect with micafungin on the growth of wild-type cells, whereas it decreased the inhibitory effect of micafungin in Δpmk1 cells, a deletion mutant of the cell wall integrity mitogen-activated protein kinase (MAPK) Pmk1. Altogether, our findings provide useful information for new potential drug combinations in the treatment of fungal infections.
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影响因子：
2.6
作者：
Brace, JL;VanderWeele, DJ;Rudin, CM
通讯作者：
Rudin, CM
影响因子：
1.8
作者：
Giusiano, G;Mangiaterra, M;Gómez, V
通讯作者：
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影响因子：
11.4
作者：
HARDWICK, KG;LEWIS, MJ;PELHAM, HRB
通讯作者：
PELHAM, HRB
影响因子：
1.9
作者：
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通讯作者：
Espinel-Ingroff, Ana
DOI：
10.1073/pnas.0902976106
发表时间：
2009-08-25
影响因子：
11.1
作者：
Furgason, Melonnie L. M.;MacDonald, Chris;Munson, Mary
通讯作者：
Munson, Mary