Mycolactone-Mediated Virulence in M. ulcerans

描述（由申请方提供）：溃疡分枝杆菌是 布鲁里溃疡的病原体，一种严重的持续性皮肤感染， 最近在西非被指定为新出现的感染。这种疾病已经 一种独特的病理学尽管有大面积的组织损伤 细菌负荷，对生物体几乎没有急性炎症反应。一 一个布鲁里溃疡可能覆盖15%的人的身体表面;唯一的 治疗方法是手术和植皮。 一种聚酮衍生的大环内酯毒素命名为菌内酯已被确定 溃疡分枝杆菌。大环内酯类是由土壤产生的次级代谢产物 细菌和真菌。它们作为细胞抑制素具有巨大的药用价值， 免疫抑制剂、抗真菌剂、抗蠕虫剂和抗生素。 菌内酯是第一个从病原体中鉴定出的大环内酯。 有证据表明，真菌内酯是负责大部分的病理， 布鲁里溃疡。菌内酯介导的表型包括细胞周期停滞， 免疫抑制和通过细胞凋亡死亡。菌内酯的基因 其合成及其作用机制是已知的。本提案的目标 是：1）克隆和测序用于分枝菌内酯生物合成的基因，2） 构建真菌内酯生产缺陷突变体，和3）开始 表征参与分枝菌内酯介导的细胞途径中的事件 使用微阵列基因表达技术进行细胞死亡和免疫抑制。 这些研究的结果应该对治疗产生重大影响 和预防布鲁里溃疡以及提供洞察潜在的作用， 聚酮化合物在其他分枝杆菌疾病如肺结核中的作用。在 此外，这项工作可能会提供有用的洞察大环内酯类细胞生物学。

DESCRIPTION (provided by the applicant): Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe persistent skin infection which has been recently designated an emerging infection in West Africa. The disease has a unique pathology. Despite extensive tissue damage and the presence of a heavy bacterial load, there is little acute inflammatory response to the organism. A single Buruli ulcer may cover 15 percent of a person's body surface; the only cure is surgery and skin grafting. A polyketide-derived macrolide toxin designated mycolactone has been identified in M ulcerans. Macrolides are produced as secondary metabolites by soil bacteria and fungi. They have enormous pharmaceutical value as cytostatins, immunosuppressants, antifungal agents, antihelminthic agents and antibiotics. Mycolactone is the first macrolide identified from a pathogen. Evidence suggests that mycolactone is responsible for most of the pathology in Buruli ulcer. Mycolactone-mediated phenotypes include cell cycle arrest, immunosuppression and death via apoptosis. Neither the genetics of mycolactone synthesis nor its mechanism of action are known. The goals of this proposal are: 1) to clone and sequence genes for mycolactone biosynthesis, 2) to construct mutants defective in mycolactone production, and 3) to begin characterizing events in the cellular pathways involved in mycolactone mediated cell death and immunosuppression using micro-array gene-expression technology. Results from these studies should have a significant impact on the treatment and prevention of Buruli ulcer as well as provide insight into potential role of polyketides in other mycobacterial diseases such as tuberculosis. In addition, this work may provide useful insight into macrolide cell biology.