Exploiting Fungal Natural Products to Discover Novel Scaffolds That Inhibit Dormant and Drug-Resistant TB

利用真菌天然产物发现抑制休眠和耐药结核病的新型支架

• 批准号: 9316820
• 负责人: Robert Henry Cichewicz
• 金额: $ 23.53万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-20 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316820
• 关键词: Address; Animal Model; Anti-Bacterial Agents; Anti-Retroviral Agents; Antibiotics; Antitubercular Agents; Bacillus (bacterium); Bacteria; Biological Assay; Cells; Chemical Structure; Chemicals; Clinical; Collection; Communicable Diseases; Coupled; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Dose; Drug resistance; Drug resistance in tuberculosis; Extreme drug resistant tuberculosis; Future; Genus Mycobacterium; Goals; Granuloma; Growth; HIV; Heritability; Hypoxia; In Vitro; Laboratories; Lead; Libraries; Modeling; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycophenolate; Natural Products; Oklahoma; Patients; Penicillins; Pharmaceutical Preparations; Phenotype; Physiological; Population; Preclinical Drug Evaluation; Property; Public Health; Pyrazinamide; Regimen; Relapse; Reporting; Resolution; Resources; Rifampin; Sampling; Soil; Source; Stress; Structure; Testing; Therapeutic; Treatment Failure; Tuberculosis; Universities; antimicrobial; base; cytotoxicity; disorder control; drug development; drug discovery; drug metabolism; efficacy study; fungus; improved; in vivo; inhibitor/antagonist; killings; macrophage; non-compliance; non-tuberculosis mycobacteria; novel; novel drug class; novel therapeutics; pathogen; phase II trial; repository; response; scaffold; screening; stem; therapeutic candidate; treatment duration; tuberculosis drugs; tuberculosis treatment

Summary Our long-term goal is to develop a novel treatment for Tuberculosis (TB) which is one of the most devastating diseases worldwide, infecting ~1/3 of the global population and claiming more than ~1.5 million lives each year. The shortcomings of currently available TB drugs underscore the urgent need to discover novel compounds to effectively treat TB patients. The current “short course” front-line regimen involves a cocktail of multiple drugs taken for 6-9 months. This protracted treatment stems from the difficulty of eradicating dormant populations of Mtb in various niches throughout the body. The emergence of Multidrug-Resistant (MDR-TB) and Extremely Drug Resistant (XDR-TB) strains of TB further complicates the control of this disease. Thus, there is an urgent need for potent drugs with novel modes of action capable of shortening the course of treatment and killing drug-resistant and dormant Mtb in vivo. To address this problem we will combine the chemical diversity of natural products (NP) and our capability to conduct whole-cell drug screening against Mtb under in vivo-like conditions to identify novel scaffolds to fuel the TB drug development pipeline. Encouraged by our discovery of numerous fungal NP active against both replicating and dormant Mtb in our screens of ~2500 fungal extracts, in Aim 1 we propose to characterize the potency and selectivity of active NP to identify high priority samples for deconvolution and identification of novel scaffolds with anti-TB activity. Our preliminary data support the hypothesis that screening NP samples under in vivo- like conditions such as our in vitro dormancy model can reveal “hit” compounds presumably acting on novel targets that are only essential, and thus vulnerable to inhibition, under stress conditions encountered in vivo. Aim 2 will focus on purifying the active components from the most potent and selective mixtures, determining their chemical structure, and conducting comprehensive analysis of antimicrobial activity and physicochemical properties. Potent and selective inhibitors of dormant, intracellular, and/or drug resistant Mtb that we identify in this project will serve as the basis for future hit-to-lead development of novel candidate therapeutics for TB.

概括 我们的长期目标是为结核病（TB）开发新的治疗方法，这是 在全球范围内，大多数毁灭性疾病，感染了约1/3的全球人口，声称更多 每年大约有150万人的生活。 迫切需要发现新型化合物以有效治疗当前的“短”。 课程“前线方案涉及多种药物的鸡尾酒，持续了6-9个月。这。 旷日持久的治疗源于MTB消除的消除的差异 各种壁ni的身体。 TB的极度耐药性（XDR-TB）菌株进一步汇总了对该疾病的控制。 因此，迫切需要采用具有新型作用模式的有效药物 缩短治疗过程，并在体内杀死耐药和休眠的MTB。 为了解决这个问题，我们将结合天然产品的化学多样性（NP）和我们的 能够在类似于体内的糖果下进行全细胞鼓药筛选MTB 确定新颖的脚手架以助长TB药物开发管道。 在我们的屏幕中，众多的真菌NP在我们的屏幕中具有重复和休眠MTB的活性 真菌提取物，在AIM 1中，我们建议表征活性NP的潜力和选择性 确定具有抗TB的新型支架的反卷积和鉴定的高优先级样本 活动。 就像我们的体外休眠模型等条件一样，大概可以揭示“命中”化合物 作用于只有必不可少的新颖目标，因此容易受到侵害的影响 在体内遇到的条件将重点放在 最有效和选择性的混合物，确定其化学结构并进行 抗菌活性和理化特性的综合分析 我们在中休眠，细胞内和/或耐药的MTB的选择性抑制剂，我们在 该项目将作为新候选人未来命中发展发展的基础 结核病的治疗剂。