Innovative technologies to transform antibiotic discovery. Project 2 Engineering antibiotic sensitization therapies

改变抗生素发现的创新技术。

• 批准号: 10463689
• 负责人: Paul Clark Blainey
• 金额: $ 168.76万
• 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/10463689
• 关键词: Acinetobacter baumannii; Affect; Animal Model; Antibiotics; Biological Products; Characteristics; Chemicals; Chemosensitization; Clinic; Clinical; Combined Antibiotics; Combined Modality Therapy; Companions; Complex; Data; Development; Dose; Drug Interactions; Drug resistance; ESKAPE pathogens; Early treatment; Engineering; Environment; Escherichia coli; Evaluation; Goals; Growth; Hand; Human; In Vitro; Klebsiella pneumoniae; Lead; Measures; Microbial Biofilms; Morbidity - disease rate; Multi-Drug Resistance; Organism; Patient Care; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Preclinical Testing; Prevalence; Program Development; Pseudomonas aeruginosa; Refractory; Regimen; Resistance; Risk; Running; Staphylococcus aureus; Testing; Therapeutic; Toxic effect; Translations; Validation; Work; antimicrobial; base; clinical candidate; drug candidate; efficacy testing; follow-up; global health; improved; in vivo; in vivo evaluation; infection rate; innovative technologies; insight; novel lead compound; novel therapeutics; pathogen; screening; small molecule; small molecule libraries; synergism

The ESKAPE pathogens continue to pose a significant global health risk due to the prevalence of multidrug resistance and widespread rates of infection. New therapies are thus highly desired, and we propose leveraging combinations of antibiotics to both improve efficacy and manage drug resistance. Optimal multi-drug regimens consider how each drug affects the efficacy of others. Synergistic multi-drug treatments against the ESKAPE pathogens may transform patient care by providing more potent synergistic therapies, allowing dosing at levels that lower the rate of drug-dependent morbidity, and quickly shrinking pathogen populations, possibly slowing drug resistance acquisition. We have developed experimental and analytical platforms to efficiently measure, analyze, and predict pairwise and high-order drug interactions, allowing us to prioritize combinations from a large numbers of drugs. We propose to build upon our platforms to accelerate the development of combination therapies against three important nosocomial ESKAPE pathogens: Acinetobacter baumannii (Ab), Klebsiella pneumonia (Kp), and Pseudomonas aeruginosa (Pa). Treatment of these ESKAPE pathogens is currently limited because of their remarkable ability to acquire drug resistance and "escape" treatment. Promising combination therapies against ESKAPE pathogens are being developed ad hoc today, illustrating the need for systematic strategies that employ this approach. To fully realize the potential of new drug candidates and optimize their use against ESKAPE pathogens, we propose to systematically explore combination therapy early in the development pipeline. We will leverage the scale and efficiency of a well-validated micro-scale screening approach to measure the efficacies and interactions of pairwise combinations among 25 antibiotics and small molecule libraries and new chemical entities including biologics and conjugates discovered in projects 1, 3, and 4. Discovery will consist of screening against resistant clinical isolates. We will rigorously validate screening hits and prioritize these by chemical progressibility, evaluation of market need, and in tests against clinical isolate panels, expanded antibiotic sets, basic toxicity assessment, and efficacy in more complex growth-niche conditions (such as host-like environmental conditions, biofilms, and in animal models). Combinations that display favorable characteristics in preliminary analyses will be subjected to further intensive mechanism-of-action and resistance acquisition studies. Based on these data, we will predict interactions with further available compounds in our hit set and test engineered higher-order combination therapies. Priority leads will be systematically optimized in a substantial medicinal chemistry effort aimed at engineering a comprehensive product characteristic profile and extending through in vivo proof of concept (PoC). We anticipate that this work will identify potent candidate drug regimens that are commercially attractive and have a strong scientific basis for translation to the clinic.

由于多药的流行，Eskape病原体继续构成严重的全球健康风险 电阻和广泛感染率。因此，新疗法是高度期望的，我们提出了利用 抗生素的组合既提高功效和管理耐药性。最佳多药方案 考虑每种药物如何影响他人的疗效。针对Eskape的协同多药治疗 病原体可能通过提供更有效的协同疗法来改变患者护理 降低了依赖药物的发病率，并迅速缩小病原体种群，可能会放缓 耐药性获取。我们已经开发了实验和分析平台以有效测量， 分析并预测成对和高级药物相互作用，使我们可以优先考虑大型组合 药物数量。我们建议在平台上建立加速组合的发展 针对三种重要的医院eskape病原体的疗法：baumannii（AB），克雷伯氏菌 肺炎（KP）和铜绿假单胞菌（PA）。这些Eskape病原体的治疗目前受到限制 由于它们具有出色的获得耐药性和“逃脱”治疗的能力。有希望的组合 如今，针对埃斯卡普病原体的疗法正在临时开发，这说明了对系统的需求 采用这种方法的策略。 为了充分意识到新药的潜力并优化了对Eskape病原体的使用，我们 建议在开发管道初期系统地探索组合疗法。我们将利用 精心验证的微型筛选方法的规模和效率，以测量效果和 25种抗生素和小分子库与新化学物质之间成对组合的相互作用 项目1、3和4中发现的生物制剂和缀合物在内的实体。发现将包括筛查 抗性临床分离株。我们将严格验证筛选命中率，并通过化学品优先 进步性，市场需求的评估以及针对临床分离株板的测试，扩展的抗生素集， 基本的毒性评估和在更复杂的生长新生条件下的功效（例如宿主样 环境条件，生物膜和动物模型）。表现出有利特征的组合 在初步分析中，将受到进一步的密集行动机理和抵抗的习得 研究。基于这些数据，我们将预测与我们的命中集和测试中进一步可用化合物的交互作用 设计的高阶组合疗法。优先线将在实质性的 药物化学工作旨在设计全面的产品特征并扩展 通过体内概念证明（POC）。我们预计这项工作将确定有效的候选药物方案 这些在商业上具有吸引力，并具有强大的科学基础，可以将其转化为诊所。