Innovative technologies to transform antibiotic discovery.

改变抗生素发现的创新技术。

基本信息

批准号：
10670154
负责人：
DEBORAH T HUNG
金额：
$ 649.55万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-07 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670154
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 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 Marketing 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 Site Synthesis Chemistry Technology Therapeutic Translating antimicrobial 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 new chemical entity 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 technology platform therapeutic candidate therapeutic development

项目摘要

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，抗生素可以说是唯一的医疗手段。比任何其他干预措施都挽救了更多的生命。然而，这种挽救生命的干预措施目前正在受到抗生素耐药性问题的威胁，该问题的速度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对人类健康的最大威胁之一。预测到 2050 年，每年可能有 1000 万人死亡，这对全球经济产生巨大影响目前的抗生素格局没有发生重大转变。尽管再次发出重要呼吁对抗生素发现的投资以及该领域活动和投资的令人鼓舞的增加，新抗生素的研发管线仍然数量稀少，尤其是具有新作用机制的药物并针对严重感染中的革兰氏阴性病原体。显然需要新的代理；然而，同样重要的是需要新颖的战略和抗生素发现平台可以克服这些障碍，并在现在和未来建立管道未来。在此，我们提议建立一个跨学科中心（抗生素转化创新中心）发现; CITADel）将迎接针对重要革兰氏菌的抗生素发现的挑战阴性病原体：铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌（一般耐碳青霉烯类肠杆菌科）两者的目标都是生产新的抗菌剂具有新的行动机制的候选人可以进入临床，并开发创新平台，创建可持续的新候选抗生素管道。 CITADel 将包括 4 个项目和一个专注于创新和协同的行政核心。需要倡导的新概念包括开发窄谱、组合或生物制剂，使用下一代测序进行基于多重目标的全细胞筛选，大规模使用液滴微流控技术进行高通量组合筛选，靶向外膜必需蛋白（以避免小分子细胞内积累的需要），利用最近的合成生物学技术创建了由天然产物组成的小分子库，其合成物是在微生物基因组中编码的，但迄今为止尚未开发，是新型病原体靶向药物缀合物，以及新颖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 将以独特的方式汇集（1）具有小型开发经验的研究人员的互补专业知识促进新型疗法开发的分子和生物制剂； (2) 创新的产生具有生物技术和制药公司治疗开发专业知识的学术界；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。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Strategies for in vitro engineering of the translation machinery

DOI：
10.1093/nar/gkz1011
发表时间：
2020-02-20
期刊：
NUCLEIC ACIDS RESEARCH
影响因子：
14.9
作者：
Hammerling, Michael J.;Kruger, Antje;Jewett, Michael C.
通讯作者：
Jewett, Michael C.

Multiplexed detection of bacterial nucleic acids using Cas13 in droplet microarrays.

DOI：
10.1093/pnasnexus/pgac021
发表时间：
2022-03
期刊：
PNAS NEXUS
影响因子：
0
作者：
Thakku, Sri Gowtham;Ackerman, Cheri M.;Myhrvold, Cameron;Bhattacharyya, Roby P.;Livny, Jonathan;Ma, Peijun;Gomez, Giselle Isabella;Sabeti, Pardis C.;Blainey, Paul C.;Hung, Deborah T.
通讯作者：
Hung, Deborah T.

Cell-Free Exploration of the Natural Product Chemical Space.

DOI：
10.1002/cbic.202000452
发表时间：
2021-01-05
期刊：
Chembiochem : a European journal of chemical biology
影响因子：
0
作者：
Bogart JW;Cabezas MD;Vögeli B;Wong DA;Karim AS;Jewett MC
通讯作者：
Jewett MC

Increasing cell‐free gene expression yields from linear templates in Escherichia coli and Vibrio natriegens extracts by using DNA‐binding proteins

使用 DNA 结合蛋白提高大肠杆菌和弧菌提取物中线性模板的无细胞基因表达产量

DOI：
10.1002/bit.27538
发表时间：
2020
期刊：
Biotechnology and Bioengineering
影响因子：
3.8
作者：
Zhu Bo;Gan Rui;Cabezas Maria D.;Kojima Takaaki;Nicol Robert;Jewett Michael C.;Nakano Hideo
通讯作者：
Nakano Hideo

Integrated genomics and chemical biology herald an era of sophisticated antibacterial discovery, from defining essential genes to target elucidation.