Broad spectrum antifungals targeting fatty acid biosynthesis

针对脂肪酸生物合成的广谱抗真菌药

• 批准号: 9813825
• 负责人: Glen Palmer
• 金额: $ 49.65万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813825
• 关键词: Affect; Anti-Bacterial Agents; Antifungal Agents; Antifungal Therapy; Aspergillus fumigatus; Bacteria; Biochemical; Biological Assay; Biological Products; Candida albicans; Cause of Death; Cells; Chemical Agents; Chemicals; Clinical; Constitution; Cryptococcus neoformans; Development; Diabetes Mellitus; Drug Kinetics; Enzymes; Fatty Acid Desaturases; Fatty Acids; Fatty-acid synthase; Generations; Growth; Human; In Vitro; Incidence; Individual; Laboratories; Lead; Libraries; Life; Lipids; Malignant Neoplasms; Mammalian Cell; Metabolic syndrome; Metabolism; Methods; Monitor; Mucous Membrane; Mycoses; Natural Products; Obesity; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Physiological; Population; Prevalence; Process; Property; Proteins; Refractory; Resistance; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; Triclosan; base; efficacy testing; fatty acid biosynthesis; fitness; fungus; high throughput screening; human disease; human pathogen; improved; in vivo; in vivo evaluation; inhibitor/antagonist; innovation; interest; isoniazid; mortality; mouse model; novel therapeutics; organizational structure; pathogenic fungus; protein expression; screening; small molecule; subcutaneous; synthetic enzyme; targeted treatment

An estimated 1.5 million people die each year from invasive fungal infections, and many millions more are afflicted by debilitating mucosal and subcutaneous mycoses. Current antifungal therapies have serious deficiencies including poor efficacy, limited spectrum of activity, patient toxicity and the emergence of resistant fungi. Consequently, mortality rates have remained disturbingly high. New and improved therapeutic options are desperately needed to improve patient outcomes and redress the rise of resistance. Yet the discovery and development of new pharmocotherapies remains a frustratingly inefficient process. The objective of phase 1 (R21) of this proposal is to apply an unconventional chemical screening strategy to identify physiologically active, and fungal selective inhibitors of fatty acid (FA) biosynthesis. Our approach will focus upon fatty acid synthase (FAS) and the Ole1p FA desaturase, both of which have a fundamentally different structural organization and functional constitution compared to their mammalian counterparts. FAS and Ole1p are both essential for the viability of infectious fungi in vivo, including the prevalent human pathogens Candida albicans and Cryptococcus neoformans. We propose to exploit these targets to develop a new class of efficacious and broad spectrum antifungal therapy. A new whole-cell based approach developed within our lab termed Target Abundance based Fitness Screening (TAFiS), will be applied to identify specific inhibitors of C. albicans FAS and Ole1p. This method facilitates the selection of chemical probes that interact with a specific target protein within intact cells, thereby combining the advantages of traditional target- and cell- based screens into a single high-throughput assay. Inhibition of FA synthesis will be confirmed through biochemical analysis of treated fungal and mammalian cells, and those with fungal selective activity identified. In phase 2 (R33), the antifungal potency, selectivity and ADME properties of lead compounds will be optimized, and structure-activity relationships established. The spectrum of activity of selected leads will also be tested against important human fungal pathogens, and to isolates resistant to current antifungal drugs. Finally, the biopharmaceutic, pharmacokinetic and toxicologic properties of selected leads will be assessed before antifungal efficacy is tested in a mouse model of disseminated fungal infection. Completion of this study will facilitate the development of a new generation of antifungal drugs that can cure invasive fungal infections that are refractory to current treatment options.

据估计，每年有150万人死于侵袭性真菌感染， 受粘膜和皮下真菌病的折磨。目前的抗真菌治疗具有严重的 这些缺陷包括疗效差、活性谱有限、患者毒性和耐药性的出现。 真菌因此，死亡率仍然高得令人不安。新的和改进的治疗选择 是迫切需要改善病人的结果和纠正耐药性的上升。然而，这一发现和 新药物疗法的开发仍然是令人沮丧的低效过程。第一阶段的目标 (R21)该建议的一个重要方面是应用非传统的化学筛选策略来识别生理上的 脂肪酸（FA）生物合成的活性和真菌选择性抑制剂。我们的方法将集中在脂肪酸 合成酶（FAS）和Ole1p FA去饱和酶，两者具有根本不同的结构 组织和功能的宪法相比，他们的哺乳动物同行。FAS和Ole1p都是 对于体内感染性真菌（包括流行的人类病原体白色念珠菌）的生存至关重要 和新型隐球菌。我们建议利用这些目标来开发一类新的有效的， 广谱抗真菌治疗我们实验室开发的一种新的基于全细胞的方法称为靶向 将应用基于拟合的适应性筛选（TAFiS）来鉴定C.白色念珠菌FAS Ole1p。这种方法有利于选择与特定靶蛋白相互作用的化学探针 在完整的细胞内，从而将传统的基于靶和基于细胞的筛选的优点结合成一个单一的 高通量测定。FA合成的抑制将通过处理的生物化学分析来证实。 真菌和哺乳动物细胞，以及鉴定的具有真菌选择活性的那些。在第2阶段（R33），抗真菌药物 先导化合物的效能、选择性和ADME性质将被优化， 建立关系。还将对选定的导联的活动谱进行测试， 人类真菌病原体和对当前抗真菌药物耐药的分离物。最后，生物制药， 在确定抗真菌疗效之前，将评估选定电极导线的药代动力学和毒理学特性。 在播散性真菌感染的小鼠模型中进行测试。完成这项研究将有助于 开发新一代抗真菌药物，可治愈难治性侵袭性真菌感染 目前的治疗方案。