RP2: Targeting genes and pathways for autophagy-dependent inhibition of bacterial infection

RP2：自噬依赖性抑制细菌感染的靶向基因和途径

• 批准号: 10364724
• 负责人: Ramnik J Xavier
• 金额: $ 135.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364724
• 关键词: Address; Agonist; Animal Model; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Therapy; Arboviruses; Autophagocytosis; Bacterial Infections; Biogenesis; CRISPR screen; Chemicals; Chemistry; Code; Collaborations; Communicable Diseases; Data; Defense Mechanisms; Development; Equilibrium; Funding; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetic study; Homeostasis; Host Defense; Human Biology; Human Genetics; Immunity; In Vitro; Infection; Lead; Listeria monocytogenes; Lysosomes; Meta-Analysis; Mucosal Immunity; Multi-Drug Resistance; Mycobacterium tuberculosis; Norovirus; Pathogenicity; Pathway interactions; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Predisposition; Public Health; Research Personnel; Role; Salmonella; Salmonella typhimurium; Shigella flexneri; Staphylococcus aureus; Therapeutic; Toxoplasma gondii; Translating; USP8 gene; Validation; Variant; Work; design; drug discovery; drug resistant bacteria; drug resistant pathogen; efficacy evaluation; efficacy study; efficacy testing; emerging pathogen; functional genomics; in vivo; in vivo Model; industry partner; innovation; insight; lead candidate; microorganism; multidisciplinary; new therapeutic target; novel; novel lead compound; pathogenic bacteria; pathogenic virus; priority pathogen; programs; proteogenomics; resistant strain; screening; small molecule; therapeutic development; therapeutic target

PROJECT SUMMARY – RP2: Emerging drug-resistant pathogens have outpaced drug discovery, which poses significant challenges for the development of safe and efficacious drugs. Our strategic approach addresses challenges in drug discovery by integrating human genetics, functional genomics, novel animal models, and innovative chemistry. Specifically, RP2 aims to develop host-directed therapeutics that harness innate intracellular defense mechanisms through induction of autophagy for the treatment of bacterial pathogens including S. Typhimurium, L. monocytogenes, S. aureus, multiple-drug-resistant strains thereof, and additional priority pathogens with RP1, RP3, and RP4. During the previous CETR funding period we have (1) completed 3 small molecule screens to identify autophagy-dependent anti-infective molecules, (2) completed several CRISPR screens to identify new targets controlling selective autophagy and lysosome homeostasis, and (3) leveraged human genetics and functional genomics to identify novel targets for therapeutic induction of antibacterial autophagy. Collectively, these studies advanced our objective of developing autophagy-directed therapeutics by generating novel lead compounds from phenotypic screens and precision targets from functional genomics. Moreover, our work has uncovered novel regulatory mechanisms governing autophagy and translated these discoveries to identify new points of entry for autophagy therapeutics. Our collaboration with RP1, RP3 and RP4 led to the discovery of small molecules that augment innate intracellular defense against diverse pathogenic microorganisms, including M. tuberculosis, S. flexneri, S. Typhimurium, arboviruses, norovirus, and T. gondii. In addition, we have partnered with Novartis to advance lead compounds directed at novel targets and to facilitate IND-enabling studies. In this CETR proposal, we will advance these autophagy-dependent anti- infective molecules using innovative chemistry (RP5) and validate new therapeutic targets from functional genomic and human genetic studies. We propose to leverage discoveries from the previous CETR Program to advance: Aim 1: medicinal chemistry to progress primary screen hits from three independent autophagy screens (LC3 puncta, NDP52-Salmonella co-localization and GPR65 agonist) to lead candidate autophagy-dependent broad-spectrum anti-infectives for in vitro and in vivo efficacy studies; Aim 2: development of targeting strategies to induce autophagy through TFEB, a master transcriptional regulator of autophagy and lysosome biogenesis genes; Aim 3: validation of novel genes identified from functional genomic and human genetic studies as therapeutic targets for antibacterial autophagy; and Aim 4: validation of novel anti-infective candidates generated by RP1-RP5 as inducers of anti-bacterial autophagy using in vitro and in vivo models. Together, our CETR team and industry partners are uniquely positioned to rapidly advance new treatments for emerging pathogens and infectious diseases.

项目摘要 - RP2：新兴药物的病原体已超过药物发现，姿势 对安全有效的药物开发的重大挑战。我们的战略方法解决 通过整合人类遗传学，功能基因组学，新型动物模型和 创新化学。具体而言，RP2旨在开发主机定向的治疗疗法 通过诱导自噬治疗细菌病原体的细胞内防御机制 包括伤寒链霉菌，单核细胞增生菌，金黄色葡萄球菌，多药抗性菌株及其额外 带有RP1，RP3和RP4的优先病原体。在上一个CORT的资金期间，我们已完成（1）3 小分子筛选以鉴定自噬依赖性抗感染分子，（2）完成了几个 CRISPR屏幕确定控制选择性自噬和溶酶体体内平衡的新目标，以及（3） 利用人类遗传学和功能基因组学，以识别用于治疗诱导的新靶 抗菌自噬。总的来说，这些研究提出了我们开发自噬导向的目标 通过从表型筛选中产生新的铅化合物和功能性靶标的新型铅化合物的治疗 基因组学。此外，我们的工作已经发现了有关自噬的新型监管机制，并翻译了 这些发现以确定自噬疗法的新入境点。我们与RP1的合作RP3 RP4导致发现了小分子，从而增强了对潜水员的先天防御 致病性微生物，包括结核分枝杆菌，S。flexneri，S。typhimurium，Arboviruses，Norovirus和 T. Gondii。此外，我们还与诺华合作，推进针对新目标的铅化合物， 促进辅助研究。在这项CORT的建议中，我们将推进这些自噬依赖性抗抗 使用创新化学（RP5）的感染性分子，并从功能上验证新的治疗靶标 基因组和人类遗传研究。我们建议利用以前的CERTON计划的发现 提前：目标1：从三个独立自噬屏幕中进行初级筛选的药物化学反应 （LC3 Puncta，NDP52-Salmonella共定位和GPR65激动剂）以领导候选自噬依赖性 用于体外和体内效率研究的广谱抗感染物；目标2：制定目标策略 通过TFEB诱导自噬，这是自噬和溶酶体生物发生的主转录调节剂 基因； AIM 3：从功能基因组和人类遗传研究中鉴定的新型基因的验证 抗菌自噬的治疗靶标；和目标4：生成的新型反感染候选者的验证 由RP1-RP5作为使用体外和体内模型的抗细菌自噬的影响者。在一起，我们的CERT团队 行业合作伙伴的独特位置，可以快速促进新兴病原体和 传染病。