Innovative technologies to transform antibiotic discovery.

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拯救了更多的生命。然而，这种拯救生命的干预现在正在进行 受到抗生素耐药性问题的威胁，这一问题的速度超过了新抗生素的发现，导致 世界卫生组织和疾控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 包括到2050年每年有1000万人死亡的可能性，这将对#年的全球经济产生巨大影响 目前的抗生素版图没有发生重大变化。尽管重新发出了重要的呼吁 在抗生素发现方面的投资以及在这一领域活动和投资的令人鼓舞的增加， 新抗生素的流水线仍然令人震惊地稀少，特别是对于具有新作用机制的药物 并以严重感染的革兰氏阴性病原体为靶标。 显然需要新的代理人；然而，同样重要的是需要新的战略和 抗生素发现平台可以克服这些障碍，并创建一条现在和进入 未来。在此，我们提出了一个跨学科的中心(Center for Innovation to Transform抗生素 发现；Citadel)，将接受针对重要革兰氏的抗生素发现的挑战 铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌 (碳青霉烯类耐药肠杆菌)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诊所，并正在开发 创新平台，创建可持续的新抗生素候选者管道。Citadel将包括 4个项目和一个注重创新和协同的行政核心。 将倡导的新概念包括开发窄谱、组合或 生物制剂，使用下一代测序的基于多重目标的全细胞筛选，大规模 利用液滴微流控技术的高通量组合筛选，靶向外源 膜必需蛋白质(避免小分子在细胞内积累的需要)，利用 最新的合成生物技术以创建由天然产物组成的小分子文库，其 合成是在微生物基因组中编码的，但到目前为止还没有被开发，新的病原体靶向药物 结合物，以及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，城堡将独一无二 汇聚(1)具有小岛屿发展中国家开发经验的调查人员的互补专业知识 分子和生物制剂推动新疗法的开发；(2)在 具有生物技术和制药公司治疗开发专业知识的学术界；以及 (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。

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.