Development and Formulation of Broad Spectrum Antimicrobials for Biodefense

描述(申请人提供)：我们计划的长期目标是开发新的广谱化疗药物，可用于第一阶段临床试验，治疗由优先病原体引起的疾病，如图拉氏方济氏菌、假鼻疽伯克霍尔德氏菌和鼠疫耶尔森菌。我们已经开发了一系列高亲和力的脂肪酸生物合成烯醇基还原酶(Fabl)酶抑制剂，它们在体外显示了对图拉氏杆菌、结核分枝杆菌和假鼻疽的效力，并在图拉热症的动物模型中发挥了作用，证实了目标和我们方法的有效性。本项目的目标是通过确定处方和给药方式以及结构修改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。最初的研究将集中在A类病原体图拉氏菌和图拉热病感染模型上，因为这是我们取得最大成功的系统。随着项目的发展，所获得的信息将被用于推动对假鼻疽杆菌和类鼻疽病感染和鼠疫杆菌动物模型的进一步研究。我们将对Fabl抑制剂进行领先优化研究，以：(I)改善药理作用和减少代谢倾向，(Ii)促进交付/生物利用度，(Iii)改善释放动力学，以及(Iv)评估替代给药途径，以优化临床前研究的候选药物，并执行提交IND申请所需的基准。我们开发体内药效增强的抑制剂的目标将通过以下具体目标来实现：目标1：处方和给药方法对PK和体内抗菌活性的影响。目的2：引入结构修饰以改善PK/PD。目标3：扩展到其他优先病原体。相关性(见说明书)：这项建议是为了加强广谱化疗药物的治疗效果，对图拉氏杆菌、假鼻疽杆菌和鼠疫杆菌感染有效。此外，这种化疗药物可用于治疗与健康有显著关系的细菌，特别是革兰氏阳性病原体，包括MRSA和革兰氏阴性病原体，包括铜绿假单胞菌、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