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

由于多种药物的流行，ESKAPE病原体继续构成重大的全球健康风险 耐药性和广泛的感染率。因此，人们非常需要新的治疗方法，我们建议利用 抗生素的组合既能提高疗效，又能控制耐药性。最优多药方案 考虑一下每种药物是如何影响其他药物的疗效的。抗ESKAPE的多药协同治疗 病原体可能会通过提供更有效的协同治疗来改变患者的护理，允许在一定水平上进行剂量 这降低了药物依赖的发病率，并迅速减少了病原体数量，可能会减缓 获得抗药性。我们已经开发了实验和分析平台来有效地测量， 分析和预测成对和高阶药物相互作用，使我们能够从大的 毒品的数量。我们建议以我们的平台为基础，加快联合的发展 鲍曼不动杆菌、克雷伯菌三种重要院内致病菌的治疗 肺炎(Kp)和铜绿假单胞菌(PA)。目前对这些ESKAPE病原体的治疗是有限的 因为它们具有非凡的抗药性和“逃脱”治疗能力。前景看好的组合 针对ESKAPE病原体的治疗方法今天正在特别开发，说明了系统性 采用这种方法的策略。 为了充分发挥候选新药的潜力并优化它们对ESKAPE病原体的使用，我们 建议在开发管道的早期系统地探索联合疗法。我们将利用 经过充分验证的微型筛查方法的规模和效率，以衡量有效性和 25种抗生素和小分子文库与新化合物的相互作用 在项目1、3和4中发现的实体包括生物制品和结合物。发现将包括筛选 对抗耐药的临床分离株。我们将严格验证筛查命中结果，并按化学物质确定优先顺序 可进展性，市场需求评估，以及在针对临床隔离小组的测试中，扩大抗生素组， 基本毒性评估，以及在更复杂的生长生态位条件下(如类寄主)的有效性 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，将受到进一步密集的作用机制和阻力的获取 学习。基于这些数据，我们将预测与命中集合中更多可用化合物的相互作用并进行测试 设计了更高级的联合疗法。优先销售线索将以实质性的方式进行系统优化 药物化学努力旨在设计一个全面的产品特征简介和扩展 通过体内概念验证(PoC)。我们预计这项工作将确定有效的候选药物方案。 在商业上有吸引力，并有强大的科学基础转化到临床上。

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.