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，可用于1期临床试验，用于治疗由优先病原体引起的疾病，如土拉弗朗西斯菌、类鼻疽伯克霍尔德菌和鼠疫耶尔森菌。我们已经开发了一系列高亲和力的脂肪酸生物合成烯酰还原酶（Fabl）抑制剂，这些抑制剂在体外表现出抗F。tularensis、M.结核病和B. pseudomallei，并且在兔热病的动物模型中具有活性，证实了靶标和我们方法的有效性。本项目的目标是通过确定诸如制剂和递送模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著提高治疗剂量。研究最初将集中在A类病原体F。土拉热和土拉菌感染模型，因为这是我们取得最大成功的系统。随着项目的发展，获得的信息将用于推动对B的其他研究。类鼻疽和类鼻疽感染动物模型和Y.鼠疫我们将对Fabl抑制剂进行先导物优化研究，以：（i）改善药理学并降低代谢倾向，（ii）促进递送能力/生物利用度，（iii）改善释放动力学，以及（iv）评估替代递送途径，以优化临床前研究的候选药物，并执行IND申请提交所需的基准。我们开发具有增强的体内功效的抑制剂的目标将通过以下具体目的实现：目的1：制剂和递送方法对PK和体内抗菌活性的影响。目的2：引入结构修饰以改善PK/PD。目标3：扩展到其他优先病原体。相关性（见说明书）：该提案旨在增强广谱化疗药物的治疗效果，对F有效。土拉菌和B. B. pseudomallei和Y.鼠疫感染此外，这样的化学治疗剂可用于治疗具有显著健康相关性的细菌剂，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B。cenocepacia、新洋葱A.鲍曼不动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