A New Class of Broad Spectrum Antifungal Agents

描述（由申请人提供）：近几十年来，各种真菌感染的发病率急剧增加，包括粘膜组织感染和危及生命的弥散性真菌病。机会性白色念珠菌是这两种感染的主要原因。最广泛使用的抗真菌疗法作用于真菌细胞内的狭窄靶点，并且具有显着的局限性，包括患者毒性，有限的配方和/或耐药性的发展。耐药白色念珠菌分离株的出现，以及内在耐药的物种，如光滑念珠菌，是一个严重的医学问题。因此，迫切需要新的和改进的治疗方案。本提案的目标是建立一类新的抗真菌药物，其作用机制与现有疗法不同。我们也将开始评估这些药物作为临床应用治疗的潜力。我们的研究表明，真菌液泡的破坏使白色念珠菌对宿主吞噬细胞高度敏感，无法侵入粘膜组织，并且在播散性感染的小鼠模型中无毒。类似的研究表明，在隐球菌性脑膜脑炎小鼠模型中，液泡是新生隐球菌定植和引起疾病所必需的。因此，哺乳动物细胞中缺乏等效的细胞器使得液泡成为选择性破坏真菌发病机制的一个有吸引力的干预点。我们设计了一种高效的高通量方法来鉴定破坏白色念珠菌液泡完整性的小分子。这将用于筛选一个包含5万种“类药物”化合物的文库。初步数据确定了0.1-0.4%的预期“命中率”，因此我们预计识别50-200个液泡破坏化合物。然后，我们将逐步选择那些最有潜力的未来临床应用。这将包括消除那些对哺乳动物细胞有毒的药物，并确认每种药物都能降低白色念珠菌的致病潜力。所有真菌都有液泡；因此，为了评估每种液泡破坏剂的“广谱”潜力，我们将测试对其他感染性真菌的活性，包括新型C.。长期目标是将新一代抗真菌药物推向临床试验。

DESCRIPTION (provided by applicant): Recent decades have seen a dramatic increase in the incidence of a diverse range of fungal infections, including those of mucosal tissues and life threatening disseminated mycoses. The opportunist Candida albicans is a leading cause of both types of infection. The most widely used antifungal therapies act upon a narrow range of targets within the fungal cell, and have significant limitations including patient toxicity, limited formulations, and/or the development of resistance. The emergence of resistant C. albicans isolates, as well as intrinsically resistant species such as C. glabrata, is a serious medical concern. Thus there is an urgent need for new and improved treatment options. The goal of this proposal is to establish a new class of antifungal agents which act via a distinct mechanism from existing therapies. We will also begin to assess the potential of these agents as clinically applicable treatments. Our studies have demonstrated that disruption of the fungal vacuole renders C. albicans highly susceptible to host phagocytic cells, unable to invade mucosal tissue, and avirulent in a mouse model of disseminated infection. Similar studies have shown that the vacuole is essential for Cryptococcus neoformans to colonize and cause disease in a mouse model of cryptococcal meningoencephalitis. Therefore, the lack of an equivalent organelle in mammalian cells makes the vacuole an attractive intervention point to selectively disrupt fungal pathogenesis. We have devised an efficient high through-put method to identify small molecules which disrupt the integrity of the C. albicans vacuole. This will be used to screen a library of 50,000 'drug like' compounds. Preliminary data has established an expected 'hit rate' of 0.1-0.4%, thus we anticipate identifying 50-200 vacuole disrupting compounds. We will then progressively select those with the greatest potential for future clinical application. This will involve eliminating those which are toxic to mammalian cells, and confirming that each agent reduces the pathogenic potential of C. albicans. All fungi possess a vacuole; thus, in order to assess the 'broad spectrum' potential of each vacuole disrupting agent, we will test for activity against other infectious fungi including C. neoformans. The long-term goal will be to advance this new generation of antifungal agents towards clinical trials.