GUARD: A global unbiased antimicrobial discovery platform

GUARD：全球公正的抗菌药物发现平台

• 批准号: 10597948
• 负责人: ARUL JAYARAMAN
• 金额: $ 77.12万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-07 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597948
• 关键词: Acinetobacter baumannii; Address; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Antimicrobial Resistance; Back; Biological Assay; Categories; Cells; Chemicals; Clinical; Complex; Computational Biology; Consumption; Data; Development; Engineering; Ensure; Environmental Microbiology; Equilibrium; Evolution; Goals; Growth; Habitats; Harvest; Health; Human; Immune; Immune response; Infection; Infection prevention; Inflammation; Integration Host Factors; Laboratories; Lead; Methicillin Resistance; Microbe; Microfluidics; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; Multiple Bacterial Drug Resistance; Names; Natural Products; Natural Products Chemistry; Outcome; Pathology; Phenotype; Preclinical Testing; Pseudomonas aeruginosa; Qualifying; Recovery; Research; Research Personnel; Resolution; Risk; Safety; Scientist; Site; System; Systems Development; Testing; Therapeutic; Time; Toxic effect; Work; World Health Organization; antimicrobial; bacterial resistance; combat; cost; digital; drug discovery; emerging antimicrobial resistance; innovation; metabolomics; methicillin resistant Staphylococcus aureus; microfluidic technology; novel; pathogen; prevent; prototype; research clinical testing; scaffold; screening; small molecule

ABSTRACT The emergence of antimicrobial resistance (AMR) microbes has been identified by the World Health Organization (WHO) as global threats to human health and safety. Indiscriminate use of antibiotics conjoined with natural evolution has now put us in a situation where conventional antibiotics are no longer effective. To address this global crisis, new molecules to combat AMR microbes must be developed. Unfortunately, significant gaps in conventional screening approaches have prevented the efficient discovery of desired novel antibacterial or host­ dependent anti-infective (HDAI) therapeutics. This proposal will pursue the development of an innovation that enables the simultaneous screening of compounds with antimicrobial and/or HDAI therapeutic activities, thereby dramatically enhancing the target space for thwarting AMR bacteria. Specifically, a novel microfluidic system called GUARD (a Global Unbiased Antimicrobial Recovery and Discovery platform), which supports the high­ throughput, low-cost screening of environmental microbes that produce natural products (NP) that either directly kill pathogens, or that activate host HDAI activities, has been prototyped. Notably, the GUARD system will perform these assays at single-cell (digital) resolution. The goal of this project is to further develop and utilize GUARD to identify new classes of molecules that either directly kill or prevent infection by methicillin-resistant Staphylococcus aureus (MRSA) as well as multi-drug resistant Acinetobacter baumannii and Pseudomonas aeruginosa, which have been categorized as the highest global priority (i.e., "critical") by the WHO. In addition, this project will discern their mechanisms of action. With these ideas in mind, this proposal aims: Aim 1: To develop the GUARD platform and utilize it to screen more than 108 microbes from diverse habitats to identify isolates that synthesize NPs that (a) kill multidrug resistant A. baumannii, P. aeruginosa, and MRSA or induce HDAI activities that protect host cells, and (b) are non-toxic to host cells; Aim 2: To utilize sequencing and state­ of-the-art analytical chemical dereplication, lead prioritization, and small molecule purification strategies to identify novel NP scaffolds with desirable profiles; Aim 3: To evaluate the spectrum of pathogens targeted by the most promising NP antimicrobials and/or HDAIs, and the host targets of our most promising HDAI NPs. Important outcomes of this work will be the development and implementation of a novel platform and workflow for the discovery of molecules that defeat AMR microbes, and the delivery of several novel NPs that can be advanced for further pre-clinical testing and clinical evaluation.

摘要 抗菌素耐药(AMR)微生物的出现已被世界卫生组织(WHO)确定为对人类健康和安全的全球威胁。不分青红皂白地使用抗生素，结合自然进化，现在已经把我们置于传统抗生素不再有效的境地。为了解决这一全球危机，必须开发新的分子来对抗AMR微生物。不幸的是，传统筛查方法中的重大缺陷阻碍了有效发现所需的新型抗菌或宿主依赖抗感染(HDAI)疗法。这项提议将寻求开发一种创新，使具有抗微生物和/或HDAI治疗活性的化合物能够同时筛选，从而极大地增强挫败AMR细菌的目标空间。具体地说，一种名为GARD(全球无偏向抗菌素恢复和发现平台)的新型微流控系统已经形成原型，该系统支持高通量、低成本地筛选产生直接杀死病原体或激活宿主HDAI活性的天然产物(NP)的环境微生物。值得注意的是，警卫系统将在单细胞(数字)分辨率下执行这些分析。该项目的目标是进一步开发和利用GARD来识别直接杀死或预防甲氧西林耐药金黄色葡萄球菌(MRSA)以及多重耐药鲍曼不动杆菌和铜绿假单胞菌感染的新型分子，这些分子已被世界卫生组织归类为全球最高优先事项(即“关键”)。此外，该项目还将了解它们的作用机制。考虑到这些想法，本提案的目标是：目标1：开发防护平台并利用它来筛选来自不同生境的108多种微生物，以鉴定合成NPs的菌株，这些NPs(A)杀死耐多药鲍曼不动杆菌、铜绿假单胞菌和MRSA或诱导保护宿主细胞的HDAI活性，以及(B)对宿主细胞无毒；目标2：利用测序和最新的分析化学去复制、铅优先排序和小分子纯化策略来鉴定具有理想特征的新型NP支架；目的3：评估最有希望的NP抗菌药和/或HDAI靶向的病原体的谱，以及我们最有希望的HDAI NPs的宿主靶标。这项工作的重要成果将是开发和实施一种新的平台和工作流程，用于发现击败AMR微生物的分子，并交付几种可用于进一步临床前测试和临床评估的新型NPs。