New therapeutics for the treatment of Acinetobactor baumannii infections.

描述（由申请人提供）：不动杆菌是严格需氧、非发酵的革兰氏阴性杆菌，对人类健康有重大影响，特别是鲍曼不动杆菌。它们是临床重要感染的罪魁祸首，这些感染会导致多种疾病，包括肺炎、皮肤和伤口感染、菌血症和脑膜炎。此外，鲍曼不动杆菌的生物膜与囊性纤维化、牙周炎和尿路感染有关，因为这种细菌能够在留置医疗器械中定植。耐药鲍曼不动杆菌的增加严重限制了治疗的治疗选择，人们普遍认为迫切需要新的治疗方法，这是这次STTR的主要目标。我们在宾夕法尼亚大学和RMH科学的实验室专门针对新的抗菌药物发现的氧化磷酸化（OxPhos）系统。OxPhos系统是细菌以ATP形式产生能量的主要途径，是细菌生存的重要过程。细菌OxPhos的成分与线粒体的成分之间存在显著差异，两者之间的序列同源性较低，表明通过这种方法进行病原体特异性治疗是可能的。高通量筛选活动进行鉴定鲍曼不动杆菌OxPhos抑制剂。我们已经从HTS中发现了多种药物样支架，可以选择性地杀死鲍曼芽胞杆菌，其最小抑制浓度（MIC）值低至8 mg/mL。我们已经确定这些化合物的目标是1型NADH脱氢酶（NDH-1）。在这项资助中，我们Fox Chase化学多样性中心公司在Aim 1中提出进行迭代药物化学来鉴定具有有效和选择性抗菌活性的化合物。药物化学设计基于对HTS中top hits的分析，并在此基础上进行了全面的文献综述，使用业界计算的生物物理性质标准，如拓扑极表面积和Log P，并考虑我们创造新知识产权的能力。目标2涉及迭代体外生物测试分析，以跟踪生化和细胞活动，包括系统的分析

DESCRIPTION (provided by applicant): Acinetobacter are strictly aerobic, non-fermentative Gram-negative bacilli that are of major concern in human health, in particular the species Acinetobacter baumannii. They are responsible for clinically important infections that cause a wide variety of maladies including pneumonia, skin and wound infections, bacteremia and meningitis. In addition, A. baumannii biofilms have been implicated in cystic fibrosis, periodontitis and urinary tract infections, due to the bacteria's ability to colonize indwelling medical devices. The rise in antibiotic resistant A. baumannii has severely limited the therapeutic options for treatment, and it is widely recognized that new therapies are desperately needed which is the major goal of this STTR. Our laboratories at the University of Pennsylvania and RMH Sciences specialize in targeting the oxidative phosphorylation (OxPhos) system in new antibacterial drug discovery. The OxPhos system is the main pathway used by bacteria to produce energy in the form of ATP and is an essential process for bacterial survival. There are marked differences between the components of the bacterial OxPhos with those of mitochondria and low sequence homology between the two, suggesting that pathogen-specific therapy by this approach is possible. A high throughput screening campaign was conducted to identify A. baumannii OxPhos inhibitors. We have discovered multiple drug-like scaffolds from the HTS that selectively kill A. baumannii, with minimal inhibitory concentration (MIC) values as low as 8 mg/mL. We have identified the target of these compounds to be type 1 NADH dehydrogenase (NDH-1). In this grant, we at the Fox Chase Chemical Diversity Center, Inc. propose in Aim 1 to perform iterative medicinal chemistry to identify compounds with potent and selective antibacterial activity. Medicinal chemistry design is based upon analysis of the top hits from the HTS on which thorough literature review has been conducted, using calculated biophysical properties standard in the industry such as topological polar surface area and Log P as well as considerations of our ability to create new intellectual property. Aim 2 involves iterative in vitr biological testing assays to track biochemical and cellular activity including systematic assays to determine the exact molecular basis for the mechanism of action. Importantly, we will confirm the lack of effect in the OxPhos associated with mammalian mitochondria, as already demonstrated for our current hits. In Aim 3, we will utilize standard target validation and hit to lead in vitro and in vivo ADME properties including pharmacokinetic evaluation in mice, and obtain >3 advanced leads from diverse chemotypes with acceptable ADME and PK properties. Our goal is to produce potent, selective and drug-like advanced leads with MIC values of < 0.4 mg/mL (< 0.1 mg/mL preferred). At the completion of this proposal, we will be well suited to transition to Phase II of the STTR program, involving the pre-clinical and clinical development activities required to eventually validate the approach in patients, pursuant to eventual partnering with a major pharmaceutical company and commercialization.