Innovative technologies to transform antibiotic discovery.

改变抗生素发现的创新技术。

• 批准号: 10463686
• 负责人: DEBORAH T HUNG
• 金额: $ 662.11万
• 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/10463686
• 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·弗莱明发现青霉素以来，抗生素一直是可以说是唯一的医疗手段。 比其他任何干预措施都挽救了更多的生命。然而，这种拯救生命的干预措施现在正在 抗生素耐药性问题的威胁超过了新抗生素的发现，导致 世界卫生组织和疾病预防控制中心宣布抗生素耐药性是人类健康的最大威胁之一。预测 包括到2050年每年有1000万人死亡的可能性，这将对全球经济产生巨大影响， 当前抗生素格局没有发生重大变化。尽管再次发出重要呼吁， 在抗生素发现方面的投资以及该领域活动和投资的令人鼓舞的增加， 新抗生素的管道仍然令人担忧的稀少，特别是对于具有新作用机制的药物 并且针对严重感染中的革兰氏阴性病原体。 显然，需要新的药物;然而，同样重要的是需要新的策略， 抗生素发现平台，可以克服这些障碍，创造一个管道，现在和进入 未来在此，我们提出了一个跨学科中心（中心创新转化抗生素 发现; CITADel），这将承担抗生素发现的挑战，对重要的革兰氏 阴性病原体铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌 （一般为碳青霉烯类耐药肠球菌科）， 候选人与新的行动机制，可以进展到诊所，并发展 创新平台，以创建新抗生素候选物的可持续管道。CITADel将包括 4个项目和一个行政核心，将侧重于创新和协同作用。 新的概念，以支持包括发展窄频谱，组合，或 生物制剂，使用下一代测序的基于多靶点的全细胞筛选， 使用液滴微流控技术的高通量组合筛选，靶向外 膜必需蛋白（以避免小分子细胞内积累的需要）， 最近的合成生物学技术，以创建由天然产物组成的小分子文库， 合成在微生物基因组中编码，但迄今为止是未开发的新型病原体靶向药物 偶联物，和新的大环化化学和蛋白质工程策略，其中每一个 解决阻碍抗生素发现工作的许多关键障碍。重要的是，CITADel将独特地 （1）将具有开发小型 分子和生物制剂，以促进新疗法的发展;（2） 在生物技术和制药公司中具有治疗开发专业知识的学术界;以及 (3)临床传染病、监管和商业化专业知识，以及基础科学专业知识。