New therapeutics for the treatment of Acinetobactor baumannii infections.

治疗鲍曼不动杆菌感染的新疗法。

• 批准号: 8597861
• 负责人: Allen Bernard Reitz
• 金额: $ 30万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597861
• 关键词: ATP Synthesis Pathway; Acinetobacter; Acinetobacter baumannii; Aerobic; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Area; Bacillus (bacterium); Bacteremia; Bacteria; Biochemical; Biological Assay; Biological Testing; Caco-2 Cells; Cell Line; Cells; Chemicals; Clinical; Clinical Trials; Cystic Fibrosis; Cytochrome P450; Cytochrome c Reductase; Data; Development; Drug Design; Drug Industry; Drug Kinetics; Drug resistance; Drug usage; Evaluation; Excretory function; Foxes; Goals; Grant; Half-Life; Health; Human; Imidazole; Imines; In Vitro; Industry; Infection; Infectious Skin Diseases; Inhibitory Concentration 50; Intellectual Property; Investigation; Laboratories; Lead; Legal patent; Libraries; Liver Microsomes; Mammalian Cell; Medical Device; Membrane; Meningitis; Metabolism; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Mitochondria; Molecular; Molecular Biology Techniques; Monitor; Mus; Nosocomial Infections; Oxidative Phosphorylation; Pathway interactions; Patients; Pennsylvania; Periodontitis; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma Proteins; Pneumonia; Process; Property; Protein Binding; Qualifying; Relative (related person); Research; Research Personnel; Review Literature; Science; Sequence Homology; Series; Site; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Solubility; Source; Structure-Activity Relationship; Submitochondrial Particles; Surface; System; Therapeutic; Therapeutic Index; Toxic effect; Triage; Universities; Urinary tract infection; Validation; Wound Infection; absorption; antimicrobial; aqueous; base; commercialization; cross reactivity; cytotoxicity; design; drug discovery; experience; high throughput screening; improved; in vivo; inhibitor/antagonist; innovation; interest; killings; member; mortality; novel; novel strategies; novel therapeutics; pathogen; pre-clinical; programs; public health relevance; scaffold; screening; small molecule

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.

描述(由申请人提供)：不动杆菌是严格意义上的需氧、非发酵革兰氏阴性杆菌，对人类健康有重大影响，尤其是鲍曼不动杆菌。它们是导致各种疾病的临床重要感染的罪魁祸首，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上定植。鲍曼不动杆菌耐药性的增加严重限制了治疗的选择，人们普遍认为迫切需要新的治疗方法，这是STTR的主要目标。我们在宾夕法尼亚大学和RMH Science的实验室专门针对新药发现中的氧化磷酸化(OxPhos)系统。OxPhos系统是细菌以ATP形式产生能量的主要途径，是细菌生存的必要过程。细菌OxPhos的组成与线粒体的组成有显著差异，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。对鲍曼不动杆菌OxPhos抑制剂进行了高通量筛选。我们从HTS中发现了多种选择性杀灭鲍曼不动杆菌的类药物支架，最低抑菌浓度(MIC)低至8 mg/mL。我们已经确定这些化合物的靶标是1型NADH脱氢酶(NDH-1)。在这笔赠款中，我们福克斯大通化学多样性中心，Inc.在Aim 1中建议进行迭代药物化学，以确定具有强大和选择性抗菌活性的化合物。药物化学设计是基于对HTS中最热门的产品进行分析的基础上进行的，在此基础上进行了全面的文献回顾，使用了行业中计算的生物物理特性标准，如拓扑极表面积和对数P，以及考虑到我们创造新知识产权的能力。目标2涉及VITR生物测试分析中的迭代，以跟踪生化和细胞活动，包括系统分析 确定作用机制的确切分子基础。重要的是，我们将证实与哺乳动物线粒体相关的OxPhos缺乏作用，就像我们目前的Hit所证明的那样。在目标3中，我们将利用标准靶标验证和HIT来引导体外和体内的ADME性质，包括在小鼠体内的药代动力学评估，并从具有可接受的ADME和PK性质的不同化学类型中获得&gt；3高级引线。我们的目标是生产高效、选择性和类药物的先进引线，其MIC值为&lt；0.4 mg/mL(首选&lt；0.1 mg/mL)。在这项提议完成后，我们将非常适合过渡到STTR计划的第二阶段，包括临床前和临床开发活动，根据最终与一家主要制药公司的合作和商业化，最终在患者中验证该方法。

项目成果

Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents.

鲍曼不动杆菌 OxPhos 抑制剂作为选择性抗感染剂。

• DOI: 10.1016/j.bmcl.2014.11.020
• 发表时间: 2015
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Rubin,Harvey;Selwood,Trevor;Yano,Takahiro;Weaver,DamianG;Loughran,HMarie;Costanzo,MichaelJ;Scott,RichardW;Wrobel,JayE;Freeman,KatieB;Reitz,AllenB
• 通讯作者: Reitz,AllenB