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.

摘要 我们的长期目标是开发一种新的结核病治疗方法，这是 世界上最具破坏性的疾病，感染了全球约三分之一的人口，并声称更多 每年有150多万人丧生。目前可用的结核病药物的缺点突显了 迫切需要发现新的化合物来有效治疗结核病患者。当前的“空头” 课程“一线疗法包括6-9个月服用多种药物的鸡尾酒。这 旷日持久的治疗源于难以根除结核分枝杆菌的休眠种群 全身各处都有不同的壁龛。出现多药耐药(耐多药结核病)和 极端耐药结核病(XDR-TB)菌株使这种疾病的控制进一步复杂化。 因此，迫切需要具有新作用模式的强效药物。 缩短疗程，体内杀灭耐药、潜伏的结核分枝杆菌。 为了解决这个问题，我们将结合天然产物(NP)的化学多样性和我们的 在类似体内的条件下进行针对结核分枝杆菌的全细胞药物筛选的能力 确定新的支架，为结核病药物开发管道提供燃料。受到我们的发现的鼓舞 在我们的~2500个屏幕上，有许多真菌NP对复制和休眠的结核分枝杆菌具有活性 真菌提取物，在目标1中，我们建议表征活性NP对 识别高优先级样品以进行去卷积和鉴定新型抗结核支架 活动。我们的初步数据支持这样的假设，即在体内筛选NP样本- 在类似的条件下，比如我们的体外休眠模型，我们可以推测出“成功”的化合物 作用于新的目标，这些目标只是基本的，因此在压力下容易受到抑制 在体内遇到的情况。目标2将专注于从 最有效和最有选择性的混合物，确定其化学结构，并传导 抗菌活性和理化性质的综合分析。强大而有力 我们确定的休眠、细胞内和/或耐药结核分枝杆菌的选择性抑制剂 该项目将作为未来开发新候选人的点击到领先的基础 结核病治疗学。