Targeting hybrid histidine kinase for broad spectrum antifungal therapy

描述(由申请人提供)：这项挑战奖助金涉及广泛的挑战领域(03)“生物标记物的发现和验证”。挑战主题为03-AI-101，题为“可能导致开发具有广谱活性的抗菌剂的新病原体或宿主靶标的识别、表征和评估”。该提案的标题是：靶向杂交组氨酸激酶进行广谱抗真菌治疗。尽管严重的真菌感染日益流行，但我们缺乏抗真菌药物，大多数药物由于与共享的哺乳动物宿主靶点发生交叉反应而充满毒性，并且在过去的十年中只开发了一类新的抗真菌药物。这一建议旨在利用最近的一项开创性发现，即混合组氨酸激酶调节真菌中的二态和毒力的全球控制。我们假设杂合组氨酸激酶是开发抗真菌药物治疗患者的理想靶点。这个新的靶点提供了该领域为开发广谱抗真菌药物而一直在寻找的许多特征，因为它在整个真菌王国中高度保守，并且不存在于人类基因组中。我们提供了强有力的初步数据支持这一新的药物靶点的概念和可行性。我们拥有强大的药物发现基础设施，用于开发抗真菌药物，校园领导人是这项拨款的联合研究员，他们提供关键领域的专业知识和设施支持，从真菌和化学生物学、药物制药到涉及体外和体内动物研究的药物先导优化。我们的方法提供了一个强大的互补策略，提供了一个基于细胞的报告系统，用于识别需要信号通路才能实现其作用模式的化合物(目标1)，以及一个药效团3-D模型，以在整个王国的不同属的病原真菌中找到直接作用于这些靶点的化合物(目标2和3)。我们预计，这项工作最终将导致针对这一途径中的多个步骤的抗真菌药物，并有效地治疗人类乃至植物中广泛的严重真菌感染。 与公共卫生相关：在过去10年里，美国真菌感染的数量急剧上升，在每年的死亡原因中已跻身前10名，部分原因是缺乏有效的抗真菌药物。这项建议通过寻求识别、表征和利用病原真菌中的新药物靶标来开发有效的新抗真菌药物，从而满足了公共卫生的需要。

DESCRIPTION (provided by applicant): This challenge grant addresses the broad challenge area (03) "Biomarker Discovery and Validation". The challenge topic is 03-AI-101, entitled "Identification, characterization and evaluation of novel pathogen or host targets that may lead to the development of antimicrobials with broad-spectrum activity." The title of the proposal is: Targeting hybrid histidine kinase for broad-spectrum antifungal therapy. Despite the growing prevalence of severe fungal infections, we have a paucity of anti-fungal drugs, most of them are fraught with toxicity due to cross-reactivity with shared mammalian host targets, and only one new class of anti-fungal has been developed in the last decade. This proposal is designed to capitalize on a recent path-breaking discovery that a hybrid histidine kinase regulates global control of dimorphism and virulence in fungi. We hypothesize that hybrid histidine kinase represents an ideal target for the development of anti- fungal drugs to treat patients. This new target offers many features that the field has been seeking for development of broad-spectrum anti-fungal drugs, since it is highly conserved throughout the fungal kingdom and is not present in the human genome. We provide strong preliminary data supporting the concept and feasibility of this novel drug target. We have in place a strong drug discovery infrastructure for developing anti-fungal drugs, with campus leaders who are co-investigators on this grant, offering expertise in key areas and facility support, ranging from fungal and chemical biology, medicinal pharmacy, and drug lead optimization involving in vitro and in vivo animal studies. Our approach offers a powerful complimentary strategy that provides a cell based reporter system for identifying compounds that require the signaling pathway for their mode of action (aim 1), together with a pharmacophore 3-D model to find compounds that directly act on these targets in pathogenic fungi of divergent genera throughout the kingdom (aims 2 and 3). We expect that this work will ultimately lead to anti-fungal drugs that target multiple steps in this pathway, and are effective at treating a broad range of serious fungal infections in humans and perhaps plants. PUBLIC HEALTH RELEVANCE: The number of fungal infections has risen dramatically in the United States over the last 10 years, and has reached the top 10 in causes of annual mortality in part because of the lack of efficacious anti-fungal drugs. This proposal addresses that public health need by seeking to identify, characterize and capitalize on a novel drug target in pathogenic fungi for the development of effective new anti-fungal drugs.