Innovative technologies to transform antibiotic discovery.

改变抗生素发现的创新技术。

• 批准号: 10242000
• 负责人: DEBORAH T HUNG
• 金额: $ 673.54万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242000
• 关键词: Academia; Acinetobacter baumannii; Adjuvant; Advanced Development; Anabolism; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bacterial Antibiotic Resistance; Bacterial Infections; Basic Science; Biochemistry; Biologic Development; Biological; Biological Products; Biology; Biophysics; Biotechnology; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chemistry; Clinic; Clinical; Clinical Trials Design; Combined Modality Therapy; Communicable Diseases; Computational Biology; Development; Discipline; Drug Delivery Systems; Drug Targeting; Engineering; Equilibrium; Future; Gene Cluster; Generations; Genomic approach; Genomics; Goals; Health; Human; In Vitro; Industry; Infection; Intervention; Investments; Klebsiella pneumoniae; Lead; Life; Malignant Neoplasms; Medical; Membrane; Membrane Proteins; Microbiology; Microfluidics; Mining; Natural Products; New Agents; Pathway interactions; Patients; Penicillins; Pharmacologic Substance; Protein Engineering; Proteins; Pseudomonas aeruginosa; Research Personnel; Research Project Grants; Resistance; Savings; Site; Synthesis Chemistry; Technology; Therapeutic; Translating; antimicrobial; base; bench to bedside; carbapenem resistance; clinical development; combinatorial; commercialization; computerized tools; design; drug resistant pathogen; economic cost; emerging pathogen; experience; genomic platform; in vivo; innovation; innovative technologies; microbial genome; microfluidic technology; microorganism; next generation sequencing; novel; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; programs; screening; small molecule; small molecule libraries; synergism; synthetic biology; targeted agent; technology development; therapeutic candidate; therapeutic development

Since Alexander Fleming's discovery of penicillin, antibiotics have been arguably the single medical intervention that has saved more lives than any other. However, this life saving intervention is now being threatened by the problem of antibiotic resistance that is outpacing the discovery of new antibiotics, resulting in the WHO and CDC declaring antibiotic resistance as one of the greatest threats to human health. Projections include the possibility of 10 million deaths per year by 2050 with tremendous impact on the global economy in the absence of a significant shift in the current antibiotic landscape. Despite important renewed calls for investment in antibiotic discovery and an encouraging increase of activity and investment in this space, the pipeline of new antibiotics remains alarmingly sparse, particularly for agents with new mechanisms of action and that target Gram-negative pathogens in serious infection. Clearly new agents are needed; however, equally important is the need for novel strategies and antibiotic discovery platforms that can overcome these barriers and create a pipeline both now and into the future. Herein, we propose an interdisciplinary center (Center for Innovation to Transform Antibiotic Discovery; CITADel) that will take on the challenges of antibiotic discovery against the important Gram negative pathogens Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae (carbapenem-resistant Enterobactericeae in general) both with the goal of producing new antimicrobial candidates with new mechanisms of action that can progress into the clinics, and developing innovative platforms to create a sustainable pipeline of new antibiotic candidates. CITADel will consist of 4 projects and an administrative core that will focus on innovation and synergy. Novel concepts to be championed include the development of narrow spectrum, combination, or biological agents, multiplexed target-based whole cell screening using next generation sequencing, massively high-throughput combinatorial screening using droplet microfluidic technologies, the targeting of outer membrane essential proteins (to circumvent the need for small molecule intracellular accumulation), leveraging recent synthetic biology technologies to create small molecule libraries consisting of natural products whose syntheses are encoded within microbial genomes but to date are untapped, novel pathogen targeting-drug conjugates, and novel macrocyclization chemistries and protein engineering strategies, with each of these tackling many of the critical barriers that hinder antibiotic discovery efforts. Importantly, CITADel will uniquely bring together (1) the complementary expertises of investigators with experience in the development of small molecules and biological agents to advance the development novel therapeutics; (2) the innovation arising in academia with the expertise in therapeutic development in biotechnology and pharmaceutical companies; and (3) clinical infectious disease, regulatory, and commercialization expertise with basic science expertise.

自从亚历山大·弗莱明（Alexander Fleming）发现青霉素以来，抗生素可以说是单一的医学 干预措施比其他任何人都挽救了更多的生命。但是，这种救生干预现在正在 受到超过发现新抗生素的抗生素耐药性问题的威胁，导致 世卫组织和疾病预防控制中心宣布抗生素抗性为对人类健康的最大威胁之一。预测 包括到2050年每年1000万人死亡的可能性，对全球经济的影响很大 当前的抗生素景观没有显着转移。尽管有重要的呼吁 对抗生素发现的投资，并鼓励在该领域的活动和投资增加， 新抗生素的管道仍然令人震惊，特别是对于具有新作用机理的代理商 该靶向严重感染中的革兰氏阴性病原体。 显然需要新的代理；但是，同样重要的是需要新颖的策略和 抗生素发现平台可以克服这些障碍并在现在和进入 未来。在此，我们提出了一个跨学科中心（转化抗生素的创新中心 发现;城堡）将承担针对重要克的抗生素发现的挑战 阴性病原体铜绿假单胞菌，baumannii和克雷伯氏菌肺炎 （一般来说，耐碳青苯肠杆菌科 具有新的行动机制的候选人可以进入诊所并发展 创新平台，以创建新的抗生素候选者的可持续渠道。城堡将包括 4个项目和行政核心将重点放在创新和协同作用上。 要倡导的新颖概念包括狭窄频谱，组合或 生物学剂，使用下一代测序的多重目标全细胞筛选，大规模 使用液滴微流体技术的高通量组合筛选，外部的靶向 膜必需蛋白（以规避小分子细胞内积累的需求），利用 最近的合成生物学技术创建了由天然产品组成的小分子库 合成是在微生物基因组中编码的，但迄今为止尚未开发，新的病原体靶向药物 共轭物，新型的大环化学和蛋白质工程策略，其中每一种 解决阻碍抗生素发现工作的许多关键障碍。重要的是，城堡将独特 汇集（1）调查人员的补充专业知识，具有小型发展的经验 分子和生物学剂，以推动开发新型治疗剂； （2）创新 学术界拥有生物技术和制药公司治疗发展专业知识；和 （3）具有基础科学专业知识的临床传染病，监管和商业化专业知识。