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

 说明(申请人提供)：抗生素耐药性已被世界卫生组织宣布为人类健康的三大威胁之一。由多药耐药(MDR)细菌病原体引起的感染对社会造成了巨大的健康和经济影响，原因是快速获得耐药性和抗生素开发计划停滞不前造成的有效治疗选择不足。缺乏治疗选择与耐多药革兰氏阴性病原体尤其相关，如铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌，这些细菌极有可能阻碍抗生素治疗和标准的医院消毒程序。敏捷科学公司正在开发一种基于2-氨基咪唑(2-AI)支架的新型小分子，这种支架大大增加了耐多药细菌对抗生素治疗的敏感性。作为目前抗生素的辅助治疗，2-AI分子有可能为耐多药革兰氏阴性细菌感染提供更好的治疗选择。第一阶段的同等工作显示了2-AI化合物作为抗生素增强剂对抗多药耐药革兰氏阴性细菌病原体的潜力。我们的努力表明：1)两种先导化合物AGL-503和AGL-553能够降低对多药耐药革兰氏阴性菌的抗生素MIC值；2)AGL-503-美罗培南联合治疗能够提高多药耐药铜绿假单胞菌急性肺部感染模型的存活率和降低细菌负担(与单用美罗培南相比)；3)2-AI化合物具有良好的安全性和药效学特征；4)2-AI化合物通过一种新的作用机制发挥作用，延缓抗菌素耐药性。总体而言，这些数据为继续开发计划提供了强有力的支持，该计划旨在确定2-AI类分子作为治疗耐多药革兰氏阴性细菌感染的抗生素组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，以解决耐多药革兰氏阴性细菌感染带来的大量未得到满足的需求。首先，在目标1中，我们将确定前导2-AI化合物对铜绿假单胞菌、肺炎克雷伯菌和鲍曼不动杆菌的最佳抗生素组合。将使用小鼠大腿感染模式对最佳组合进行药效学评估。在目标2中，将通过非靶标面板筛选和靶标结合特性来评估AGL-503和AGL-553的脱靶效果。在AIM 1中取得最有希望结果的2-AI-抗肿瘤药物组合将在肺炎和尿路感染小鼠模型中进行安全性和有效性评估。目标3中的工作将告知候选化合物的目标产品概况，并将进行初步扩大工作，以促进将化合物的合成路线转让给合同制造组织。在这笔为期两年的拨款结束时，敏捷科学公司将宣布一种IND候选化合物并定义TPP，以促进后续的IND使能研究。

 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.