Mycolactone-Mediated Virulence in M. ulcerans

描述(申请人提供)：溃烂分枝杆菌是 布鲁里溃疡的病原体，一种严重的持续性皮肤感染，有 最近被指定为西非的一种新感染。这种疾病已经 一种独特的病理。尽管存在广泛的组织损伤和严重的 细菌负载时，对机体几乎没有急性炎症反应。一个 单个布鲁里溃疡可能覆盖一个人15%的体表；唯一的 治疗方法是手术和植皮。 一种名为霉菌内酯的聚酮衍生大环内酯毒素已被鉴定 在溃疡里。大环内酯类化合物是土壤产生的次生代谢物。 细菌和真菌。它们作为细胞抑素具有巨大的药用价值， 免疫抑制剂、抗真菌药、抗寄生虫药和抗生素。 霉菌内酯是第一个从病原体中鉴定出来的大环内酯。 有证据表明，霉菌内酯是导致 布鲁里溃疡。霉菌内酯介导的表型包括细胞周期停滞， 免疫抑制和细胞凋亡引起的死亡。无论是霉菌内酯的遗传学 合成及其作用机制尚不清楚。这项提案的目标是 是：1)克隆和测序真菌内酯生物合成的基因；2)克隆和测序 构建在木霉内酯生产中有缺陷的突变体，以及3)开始 霉菌内酯介导的细胞通路中事件的特征 使用微阵列基因表达技术的细胞死亡和免疫抑制。 这些研究的结果应该会对治疗产生重大影响 和预防布鲁里溃疡，并提供对潜在作用的洞察 聚酮在其他分枝杆菌疾病中的作用，如结核病。在……里面 此外，这项工作可能为大环内酯类细胞生物学提供有用的见解。

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.