Development of novel broad spectrum chemotherapeutics against priority pathogens

该程序的假设是Fabl，细菌脂肪酸中保守的烯酰还原酶， 生物合成途径，是开发具有广谱的临床前先导化合物的靶点 对优先病原体的活性，包括F. tularensis，B. B. pseudomallei和Y.鼠疫基于此 方法，我们已经开发出对来自F.土拉热， 8.假鼻疽值得注意的是，我们已经在兔热病动物模型中证明了疗效。 受到这一进展的鼓舞，并由于需要开发针对其他优先事项的化疗药物， 病原体，我们将扩大我们的研究，包括开发有效的体内抗菌剂 对6。pseudomallei和Y.鼠疫我们的总体目标是迅速将先导化合物转化为动物 用于有效性试验的感染模型，具体目的如下： 目的1：合理优化先导化合物对F。土拉热。我们将设计并合成 我们的后续几代先导化合物使用来自分子建模的SAR信息， 抗全菌活性和在动物中的功效以及生物利用度研究。 目的2：体外和体内抗B的抗菌活性。假鼻疽的体外活性 目前二苯醚类化合物对8.将通过测定（i）以下各项的IC 50来评估假鼻疽： 8.抑制（ii）抗细菌活性（MIC和MBC），（iii）毒性， PK/PD和输送能力。选定的化合物将在8个月内进行疗效试验。pseudomallei 感染的动物模型。 目标3：扩展到Y。鼠疫我们将扩大我们的抗菌发现努力，包括病原体Y。 鼠疫将使用已确立的方法和具有适当活性的化合物进行检测 将在感染的动物模型中进行评估。 该研究项目符合RMRCE细菌治疗综合研究重点，并将 直接与RP 2.1、RP 2.2、RP 2.5和RP 2.6交互，并利用Core C和Core E的资源。

The hypothesis of this program is that Fabl, the conserved enoyl reductase enzyme in the bacterial fatty acid biosynthesis pathway, is a target for the development of preclinical lead compounds with broad spectrum activity against priority pathogens, including F. tularensis, B. pseudomallei, and Y. pestis. Based on this approach, we have developed inhibitors with potent activity against the Fabl enzyme from F. tularensis and 8. pseudomallei. Significantly, we have demonstrated efficacy in an animal model of tularemia. Encouraged by this progress and due to the need to develop chemotherapeutics against other priority pathogens, we will extend our studies to include the development of potent in vivo antibacterial agents against 6. pseudomallei and Y. pestis. Our overall goal is to rapidly progress lead compounds into animal models of infection for efficacy testing with the following Specific Aims: Aim 1: Rational Optimization of Lead Compounds Against F. tularensis. We will design and synthesize subsequent generations of our lead compounds using SAR information derived from molecular modeling, activity against whole bacteria and efficacy in animals and bioavailability studies. Aim 2: In Vitro and In Vivo Antibacterial Activity against B. pseudomallei. The in vitro activity of the current diphenyl ether compounds against 8. pseudomallei will be assessed by determining (i) the IC50 for inhibition of the 8. pseudomallei Fabl enzyme (FablBpm), (ii) antibacterial activity (MIC and MBC) (iii) toxicity, PK/PD and deliverability. Selected compounds will be progressed to efficacy testing in the 8. pseudomallei animal model of infection. Aim 3: Extension to Y. pestis. We will extend our antibacterial discovery efforts to include the pathogen Y. pestis. Testing will be conducted using the established approach and compounds with appropriate activity will be evaluated in animal models of infection. This research project fits within the RMRCE Integrated Research Focus on Bacterial Therapeutics, and will interact directly with RP 2.1, RP 2.2, RP 2.5 and RP 2.6, and utilize the resources of Core C and Core E.