Small molecules as antibiotic potentiating agents against multi-drug resistant Gram-negative infections

小分子作为抗生素增强剂对抗多重耐药革兰氏阴性菌感染

基本信息

批准号：
8977618
负责人：
Daina Zeng
金额：
$ 64.11万
依托单位：
AGILE SCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977618
关键词：
Acinetobacter Acinetobacter baumannii Acute Address Adjuvant Therapy Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Bacteria Bacterial Infections Bacterial Interference Binding Centers for Disease Control and Prevention (U.S.)Cessation of life Chemosensitization Combined Antibiotics Combined Modality Therapy Contracts Crystallography Data Defense Mechanisms Development Disinfection Drug Formulations Drug Kinetics Drug resistance Evaluation Future Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Grant Health Health Care Costs Hospitals Human Infection Investigational Drugs Klebsiella pneumonia bacterium Lead Lung Maximum Tolerated Dose Meropenem Metabolic Minimum Inhibitory Concentration measurement Modeling Multi-Drug Resistance Mus OmpR protein Performance Pharmacodynamics Pharmacologic Substance Phase Plasma Proteins Pneumonia Predisposition Prevalence Procedures Program Development Property Protein Binding Pseudomonas aeruginosa Resistance Route Safety Science Societies Solutions Structure System Technology Therapeutic Thigh structure Urinary tract infection Work World Health Organization base combat disorder prevention drug candidate drug resistant bacteria economic impact exhaust health economics improved in vivo novel pathogen pre-clinical programs public health relevance scaffold scale up signal processing small molecule

项目摘要

DESCRIPTION (provided by applicant): Antibiotic resistance has been declared one of the three greatest threats to human health by the World Health Organization. Infections caused by multi-drug resistant (MDR) bacterial pathogens create substantial health and economic impacts on society due to the lack of effective therapeutic options created by the rapid acquisition of resistance and stagnant antibiotic development programs. This lack of treatment options is particularly relevant for MDR Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumanii and Klebsiella pneumoniae, which have shown a great propensity to thwart antibiotic treatments and standard hospital disinfection procedures. Agile Sciences is developing a novel class of small molecules, based on a 2-aminoimidazole (2-AI) scaffold, that substantially increase the susceptibility of MDR bacteria to antibiotic therapies. As an adjuvant therapy to current antibiotics, the 2-AI molecules have the potential to provide a much improved treatment option for MDR Gram-negative bacterial infections. Phase I equivalent work has displayed the potential of 2-AI compounds as antibiotic potentiating agents against MDR Gram-negative bacterial pathogens. Our efforts have shown that: 1) two lead compounds, AGL- 503 and AGL-553, are able to lower the antibiotic MIC values against MDR Gram-negative bacteria; 2) an AGL-503-meropenem combination therapy has the ability to enhance survival and decrease bacterial burden (compared to meropenem alone) in a MDR P. aeruginosa acute lung infection model; 3) 2-AI compounds possess favorable safety and pharmaceutical profiles; and 4) 2-AI compounds act via a novel mechanism of action that retards antimicrobial resistance. Collectively, this data provides strong support for a continued development program to define the potential therapeutic utility of the 2-AI class of molecules as an antibiotic combination therapy for treating infections caused by MDR Gram-negative bacteria. In Phase II, we will focus development of the 2-AI class of molecules to address the substantial unmet need posed by MDR Gram-negative bacterial infections. First, in Aim 1, we will identify the optimal antibiotic combinations for the lead 2-AI compounds against P. aeruginosa, K. pneumoniae, and A. baumanii. The optimal combinations will be evaluated for pharmacodynamics using the mouse thigh infections mode. In Aim 2, the off-target effects of AGL-503 and AGL-553 will be evaluated through off-target panel screens and characterizations of target binding. The 2-AI-antibitoic combination with the most promising results in Aim 1 will be evaluated for safety and efficacy in pneumonia and urinary tract infection murine models. The efforts in Aim 3 will inform the target product profile (TPP) of the candidate compound, and preliminary scale-up work will be performed to facilitate transfer of the synthetic route of the compound to a contract manufacturing organization. At the conclusion of this two-year grant, Agile Sciences will have declared an IND candidate compound and defined the TPP so as to facilitate follow-on IND-enabling studies.

描述（由申请人提供）：抗生素耐药性已被世界卫生组织宣布为对人类健康的三大威胁之一，由多重耐药（MDR）细菌病原体引起的感染对社会造成巨大的健康和经济影响。由于耐药性的快速获得和抗生素开发计划的停滞而导致缺乏有效的治疗选择，这种治疗选择的缺乏对于耐多药革兰氏阴性病原体（例如铜绿假单胞菌）尤其重要。鲍曼不动杆菌和肺炎克雷伯菌表现出极大的阻碍抗生素治疗和标准医院消毒程序的倾向，Agile Sciences 正在开发一种基于 2-氨基咪唑 (2-AI) 支架的新型小分子，可大大提高抗生素治疗和标准医院消毒程序的效果。 MDR 细菌对抗生素治疗的敏感性。作为当前抗生素的辅助疗法，2-AI 分子有可能为 MDR 提供大大改进的治疗选择。革兰氏阴性细菌感染。第一阶段的等效工作显示了 2-AI 化合物作为对抗 MDR 革兰氏阴性细菌病原体的抗生素增强剂的潜力。我们的努力表明：1）两种先导化合物，AGL-503 和 AGL-553。，能够降低针对 MDR 革兰氏阴性菌的抗生素 MIC 值；2) AGL-503-美罗培南联合疗法能够提高生存率并减少细菌负担（与单独使用美罗培南相比）在耐多药铜绿假单胞菌急性肺部感染模型中；3) 2-AI 化合物具有良好的安全性和药物特性；4) 2-AI 化合物通过一种新的作用机制发挥作用，可延缓抗菌素耐药性。持续开发计划，以确定 2-AI 类分子作为治疗 MDR 革兰氏阴性菌引起的感染的抗生素联合疗法的潜在治疗效用。在第二阶段，我们将重点开发 2-AI 类分子。首先，在目标 1 中，我们将确定针对铜绿假单胞菌、肺炎克雷伯菌和鲍曼不动杆菌的先导 2-AI 化合物的最佳抗生素组合。将使用小鼠大腿感染模式评估最佳组合的药效学。在目标 2 中，将通过脱靶面板筛选评估 AGL-503 和 AGL-553 的脱靶效应。目标结合的特征。目标 1 中最有希望的结果将在肺炎和尿路感染小鼠模型中评估其安全性和有效性。目标 3 中的努力将为目标产品概况（TPP）提供信息。）的候选化合物，并将进行初步的放大工作，以促进该化合物的合成路线转移到合同生产组织。在这两年的资助结束时，敏捷科学公司将宣布一个 IND 候选化合物。并定义了TPP，以促进后续的IND研究。