Targeting hybrid histidine kinase for broad spectrum antifungal therapy

靶向混合组氨酸激酶进行广谱抗真菌治疗

• 批准号: 7936212
• 负责人: BRUCE Steven KLEIN
• 金额: $ 49.56万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936212
• 关键词: 3-Dimensional; Address; Agriculture; Americas; Animals; Antibiotic Resistance; Antifungal Agents; Antifungal Therapy; Area; Aspergillus; Aspergillus fumigatus; Azole resistance; Binding; Biological Assay; Biological Markers; Biology; Candida; Candida albicans; Caspofungin; Cells; Cessation of life; Chemicals; Chemistry; Communicable Diseases; Congresses; Data; Databases; Development; Disease; Docking; Drug Delivery Systems; Evaluation; Food; Galactosidase; Goals; Grant; Growth; Hand; Human; Human Genome; Hybrids; In Vitro; Individual; Industrial fungicide; Infection; Institution; Lead; Libraries; Malignant Neoplasms; Mammalian Cell; Microbe; Modeling; Molds; Molecular; Mus; Mycoses; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Pharmacy facility; Phosphotransferases; Plants; Pneumonia; Prevalence; Public Health; Reaction; Reporter; Research Infrastructure; Research Personnel; Resistance; Role; Running; Saccharomyces cerevisiae; Sepsis; Signal Pathway; Signal Transduction; Societies; Stress; Structure; System; Temperature; Testing; Toxic effect; Toxicity Tests; United States; Validation; Virulence; Work; Yeasts; antimicrobial; bacterial resistance; base; chemical genetics; cross reactivity; cytotoxic; design; dimorphism; drug discovery; fludioxonil; fungus; glucan synthase; high throughput screening; in vitro Assay; in vitro activity; in vivo; inhibitor/antagonist; insight; killings; mammalian genome; mortality; novel; pathogen; pathogenic bacteria; pharmacophore; protein-histidine kinase; public health relevance; research and development; response; sensor; small molecule; small molecule libraries; three dimensional structure; virtual

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.

描述（由申请人提供）：这项挑战赠款解决了广泛的挑战领域（03）“生物标志物发现和验证”。挑战主题是03-AI-101，标题为“对新的病原体或宿主靶标的识别，表征和评估，这些靶标可能导致具有广谱活性的抗菌剂的发展”。该提案的标题是：靶向杂种组氨酸激酶进行广谱抗真菌疗法。尽管严重的真菌感染的患病率越来越严重，但我们的抗真菌药物很少，但由于与共同的哺乳动物宿主靶标的交叉反应性，其中大多数人充满了毒性，并且在过去十年中仅开发了一类新的抗恋爱。该提案旨在利用最近破裂的发现，即混合组氨酸激酶调节对真菌中二态和毒力的全球控制。我们假设杂交组氨酸激酶是开发抗真菌药物治疗患者的理想靶标。这个新目标提供了许多领域一直在寻求开发广谱抗真菌药物的特征，因为它在整个真菌王国中都高度保守，并且不存在于人类基因组中。我们提供了强大的初步数据，以支持这个新型药物靶标的概念和可行性。我们为开发抗真菌药物提供了强大的药物发现基础设施，校园领导者是该赠款的共同投资者，在关键领域和设施支持方面提供了专业知识，范围从真菌和化学生物学，药物学，药物学以及涉及体外和体内动物研究的药物优化。我们的方法提供了一种强大的免费策略，该策略提供了一个基于细胞的记者系统，用于识别需要发挥作用方式的信号传导途径（AIM 1）以及药物团3-D模型，以查找在整个Kingdom跨国属的发散属的致病真菌中直接作用于这些目标的化合物（AIMS 2和3）。我们预计这项工作最终将导致抗真菌药物，这些药物针对该途径的多个步骤，并有效地治疗了人类和植物中广泛的严重真菌感染。 公共卫生相关性：在过去的十年中，美国的真菌感染数量在美国急剧增加，并且在年死亡率的一部分中占据了前10名，部分原因是缺乏有效的抗恋药物。该提案通过寻求识别，特征和利用病原真菌中新型药物靶标的开发有效的新抗真菌药物来解决公共卫生的需求。