Development and Formulation of Broad Spectrum Antimicrobials for Biodefense

描述（由申请人提供）：我们项目的长期目标是开发新型广谱化疗药物，用于i期临床试验，用于治疗由土拉菌Francisella tularensis，假马勒氏伯克氏菌和鼠疫杆菌等优先病原体引起的疾病。我们已经开发了一系列高亲和力的脂肪酸生物合成烯醇还原酶（Fabl）酶抑制剂，这些抑制剂在体外对土拉菌、结核分枝杆菌和假马莱杆菌具有抑制作用，并且在土拉菌病动物模型中具有活性，证实了靶点和我们方法的有效性。本项目的目标是通过确定诸如配方和递送方式以及结构修饰等因素如何影响化合物的体内抗菌活性来显着提高治疗剂量。研究最初将集中在A类病原体土拉菌病和土拉菌病感染模型上，因为这是我们最成功的系统。随着项目的发展，所获得的信息将用于推动对假芽孢杆菌、类鼻疽感染动物模型和鼠疫杆菌的进一步研究。我们将对Fabl抑制剂进行先导优化研究，以：(i)改善药理学和降低代谢负荷，（ii）促进可交付性/生物利用度，（iii）改善释放动力学，以及（iv）评估替代给药途径，以优化临床前研究候选药物，并执行提交IND申请所需的基准。我们开发具有增强体内疗效的抑制剂的目标将通过以下具体目标实现：目标1：配方和给药方法对PK和体内抗菌活性的影响。目的2：引入结构修饰以提高PK/PD。目标3：扩展到其他优先病原体。相关性（见说明书）：本建议旨在增强广谱化疗药物对土拉菌、假芽孢杆菌和鼠疫杆菌感染的疗效。此外，这些化疗药物可用于治疗与健康有重大关系的细菌制剂，特别是革兰氏阳性病原体，包括MRSA和革兰氏阴性病原体，包括cenocepacia B.、鲍曼杆菌和铜绿假单胞菌

DESCRIPTION (provided by applicant): The long term goal of our program is to develop novel broad spectrum chemotherapeutics that can be used for Phase 1 clinical trials for treating the diseases caused by priority pathogens such as Francisella tularensis, Burkholderia pseudomallei and Yersinia pestis. We have developed a series of high affinity inhibitors of the fatty acid biosynthesis enoyl reductase (Fabl) enzyme that demonstrate in vitro potency against F. tularensis, M. tuberculosis and B. pseudomallei, and are active in an animal model of tularemia, confirming the validity of the target and of our approach. The goal of the present project is to dramatically improve the therapeutic dose by determining how factors such as formulation and modes of delivery, and structural modifications impact the in vivo antibacterial activity of the compounds. Studies will initially focus on the category A pathogen F. tularensis and the tularemia model of infection as this is the system in which we have had the most success. As the project evolves the information gained will be used to drive additional studies on B. pseudomallei and the melioidosis animal model of infection and Y. pestis. We will perform lead optimization studies on the Fabl inhibitors to: (i) improve pharmacology and reduce metabolic liability, (ii) facilitate deliverability/bioavailability, (iii) improve release kinetics, and (iv) assess alternative routes of delivery to optimize candidates for preclinical studies and performing required benchmarks for submission of an IND application. Our goal of developing inhibitors with enhanced in vivo efficacy will be achieved with the following Specific Aims: Aim 1: Effect of formulation and method of delivery on PK and in vivo antibacterial activity. Aim 2: Introduction of structural modifications to improve PK/PD. Aim 3: Extension to Other Priority Pathogens. RELEVANCE (See instructions): This proposal is to enhance the therapeutic effect of broad spectrum chemotherapeutics with efficacy against F. tularensis and B. pseudomallei and Y. pestis infections. In addition, such chemotherapeutics can be used to treat bacterial agents with significant health relevance, particularly Gram-positive pathogens, including MRSA and Gram-negative pathogens including B. cenocepacia, A. baumannii, and P. aeruginosa