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：新出现的耐药病原体的速度超过了药物发现的速度，这构成了 我们的战略方法解决了开发安全有效药物的重大挑战。 通过整合人类遗传学、功能基因组学、新型动物模型和 具体来说，RP2 旨在开发利用先天性的宿主导向疗法。 通过诱导自噬的细胞内防御机制来治疗细菌病原体 包括鼠伤寒沙门氏菌、单核细胞增生利斯特氏菌、金黄色葡萄球菌、其多重耐药菌株以及其他菌株 RP1、RP3 和 RP4 的优先病原体 在上一个 CETR 资助期间，我们已经 (1) 完成了 3 个。 小分子筛选以识别自噬依赖性抗感染分子，（2）完成了多项 CRISPR 筛选以确定控制选择性自噬和溶酶体稳态的新靶标，以及 (3) 利用人类遗传学和功能基因组学来确定治疗诱导的新靶点 总的来说，这些研究推进了我们开发自噬导向的目标。 通过表型筛选产生新型先导化合物和功能性精确靶标来进行治疗 此外，我们的工作发现了控制自噬和翻译的新调控机制。 这些发现确定了我们与 RP1、RP3 的合作的新切入点。 RP4 导致了小分子的发现，这些小分子可以增强针对多种细胞的先天防御 病原微生物，包括结核分枝杆菌、弗氏沙门氏菌、鼠伤寒沙门氏菌、虫媒病毒、诺如病毒和 此外，我们还与诺华合作开发针对新靶标的先导化合物。 为了促进 IND 支持的研究，在这个 CETR 提案中，我们将推进这些自噬依赖的抗 - 使用创新化学（RP5）研究感染性分子，并验证功能性新治疗靶点 我们建议利用之前的 CETR 计划的发现来 进展：目标 1：药物化学以推进来自三个独立自噬筛选的初级筛选命中 （LC3 puncta、NDP52-沙门氏菌共定位和 GPR65 激动剂）引导候选自噬依赖性 用于体外和体内功效研究的广谱抗感染药物目标 2：制定靶向策略； 通过 TFEB（自噬和溶酶体生物发生的主要转录调节因子）诱导自噬 基因；目标 3：验证从功能基因组和人类遗传学研究中确定的新基因 抗菌自噬的治疗靶点；目标 4：验证产生的新型抗感染候选药物 我们的 CETR 团队共同使用体外和体内模型，将 RP1-RP5 作为抗菌自噬的诱导剂。 和行业合作伙伴处于独特的地位，可以快速推进针对新兴病原体的新疗法 传染病。