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Ant Ag Chemot:开发出治疗致死性真菌感染的新型候选药物41F5

来源:生物谷 2013-10-09 22:57

2013年10月10日 讯 /生物谷BIOON/ --近日,一项刊登在国际杂志Antimicrobial Agents and Chemotherapy上的研究论文中,来自俄亥俄州立大学瓦克斯纳医学中心的研究者通过研究发现了一种化合物可以用于抗真菌药来治疗组织胞浆菌病和隐球菌病,后两者是一种耐药性的真菌感染性疾病。

一般情况下,免疫力低下的个体容易引发致死性的真菌感染,但是一种空气传播的真菌-荚膜组织胞浆菌,其可以引发组织胞浆菌病,甚至可以感染正常人群。研究者Chad Rappleye博士表示,组织胞浆菌病是一种罕见的真菌性疾病,因为任何人都可以被感染,而并不只有那些免疫力低下的人群才会被感染。在全美每年大约有10万人感染荚膜组织胞浆菌。

文章中,研究者通过进行筛选发现了候选化合物41F5,相比人类细胞,其对真菌细胞的毒性是前者的60倍;研究者目前正在研究该化合物的毒性和选择性是否可以继续增强。

荚膜组织胞浆菌在美国中西部和南部广泛扩散,专家估计生活在这个区域的人群大约有80%都暴露于该真菌中,该区域生活的艾滋病人大约有10%-25%会引发组织胞浆菌病的发生。一旦吸入这种真菌就会引发类似于上呼吸道感染的症状,而且疾病的严重性因吸入的真菌孢子而异,在一些罕见病例中,组织胞浆菌病可引起个体失明、关节痛甚至引发威胁生命的脑膜炎以及心脏疾病。(生物谷Bioon.com)

Identification of an Aminothiazole with Antifungal Activity against Intracellular Histoplasma capsulatum

Jessica A. Edwards, Megan M. Kemski and Chad A. Rappleye

As eukaryotes, fungi possess relatively few molecules sufficiently unique from mammalian cell components to be used as drug targets. Consequently, most current antifungals have significant host cell toxicity. Primary fungal pathogens (e.g., Histoplasma) are of particular concern, as few antifungals are effective in treating them. To identify additional antifungal candidates for the treatment of histoplasmosis, we developed a high-throughput platform for monitoring Histoplasma growth and employed it in a phenotypic screen of 3,600 commercially available compounds. Seven hit compounds that inhibited Histoplasma yeast growth were identified. Compound 41F5 has fungistatic activity against Histoplasma yeast at micromolar concentrations, with a 50% inhibitory concentration (IC50) of 0.87 μM, and has the greatest selectivity for yeast (at least 62-fold) relative to host cells. Structurally, 41F5 consists of an aminothiazole core with an alicyclic substituent at the 2-position and an aromatic substituent at the 5-position. 41F5 inhibits Histoplasma growth in liquid culture and similarly inhibits yeast cells within macrophages, the actual host environment of this fungal pathogen during infection. Importantly, 41F5 protects infected host cells from Histoplasma-induced macrophage death, making this aminothiazole hit compound an excellent candidate for development as an antifungal for Histoplasma infections.

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