Development of novel broad spectrum chemotherapeutics against priority pathogens

这个程序的假设是，细菌脂肪酸中保守的烯醇还原酶Fabl 生物合成途径是开发广谱临床前先导化合物的目标 对优先病原体的活性，包括图拉氏杆菌、假鼻疽杆菌和鼠疫耶尔森氏菌。在此基础上 通过这种方法，我们已经开发出了对来自F.tularensis和 8.假腮腺。值得注意的是，我们已经在图拉热症的动物模型中证明了疗效。 受到这一进展的鼓舞，并由于需要针对其他优先事项开发化疗药物 病原体，我们将扩大我们的研究范围，包括开发有效的体内抗菌剂 对6.假鼻疽和鼠疫耶尔森氏菌。我们的总体目标是快速将先导化合物转化为动物 用于有效性测试的感染模型，具体目标如下： 目的1：合理优化先导化合物防治图拉氏丝虫。我们将设计和合成 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、动物药效及生物利用度研究。 目的2：体外和体内对假鼻疽杆菌的抗菌活性。黄曲霉毒素的体外活性 目前的二苯醚化合物对8.假鼻疽的IC50将通过以下方法进行评估： 抑制8.假单胞菌Fabl酶(FablBpm)，(Ii)抗菌活性(MIC和MBC)(Iii)毒性， PK/PD和交付能力。选定的化合物将在8.假鼻孔进行有效性测试。 感染的动物模型。 目标3：鼠疫杆菌的延伸。我们将扩大我们的抗菌发现工作，以包括病原体Y。 鼠疫。将使用已建立的方法和具有适当活性的化合物进行测试 将在动物感染模型中进行评估。 这项研究项目符合RMRCE关于细菌治疗的综合研究重点，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.