Novel selective substituted aminofurazans kinase inhibitors for Drug resistant Bacteria

用于耐药细菌的新型选择性取代氨基呋喃激酶抑制剂

• 批准号: 10265333
• 负责人: ROBERT T STRIKER
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265333
• 关键词: Affect; Alkynes; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimycobacterial Agents; Back; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Biochemical; Biological Assay; Carbapenems; Cell Wall; Cells; Cessation of life; Chemosensitization; Clinical; Computer Models; Corynebacterium; Craniocerebral Trauma; Crystallization; Data; Development; Drug Design; Drug Targeting; Drug resistance; Embryonic Development; Family; Fertility; Genetic; Genus Mycobacterium; Gram-Positive Bacteria; Grant; Health; Human; Industry; Infection; Investments; Knowledge; Lead; Listeria; Microbiology; Modeling; Monobactams; Morphology; Mycobacterium tuberculosis; Nocardia; Operative Surgical Procedures; Organism; Pathway interactions; Patients; Penetration; Penicillin-Binding Proteins; Penicillins; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphotransferases; Property; Propionibacterium; Propionibacterium acnes; Protein-Serine-Threonine Kinases; Proteins; Resolution; Resources; Science; Signal Transduction; Skin; Soil; Structure; Structure-Activity Relationship; Surgical Wound Infection; Testing; Time; Toxic effect; Toxicity Tests; Transducers; Trauma; Tuberculosis; United States; Veterans; Veterans Hospitals; Virulence Factors; Work; X ray diffraction analysis; Zebrafish; antibiotic design; antimicrobial; bacterial resistance; base; beta-Lactams; clinically significant; design; drug development; drug repurposing; drug resistant bacteria; drug testing; effectiveness evaluation; efficacy testing; functional group; improved; inhibitor/antagonist; insight; interest; kinase inhibitor; methicillin resistant Staphylococcus aureus; mutant; mycobacterial; novel; novel therapeutics; pathogen; research and development; scaffold; screening; small molecule; small molecule inhibitor; uptake

Antibiotic resistant bacteria are a major threat to human health. Each year in the United States, approximately 2 million people are infected with bacteria that are resistant to antibiotics resulting in at least 23,000 deaths. The development of novel antibiotics is needed. However, de novo antibiotic development is resource intensive. Given the poor return on investment, major pharmaceutical companies have significantly decreased antibiotic Research and Development efforts. Academic labs generally do not have access to compounds and sufficient data for rationale design. Veterans who undergo surgical procedures for trauma, including head trauma, are vulnerable to multiple surgical infection, sometimes with organisms that are unlikely to ever represent an attractive target for pharmaceutical companies. Antibiotic development that capitalizes on existing drug designwork conducted by industry, may avoid some of the expensive missteps due to poor pharmacologic properties that can inadvertently arise in the lead selection. Our approach uses structure-based computational modeling to repurpose drugs as antibiotics. Previous work in our lab demonstrated that inhibition of a Listeria kinase, belonging to a family of Penicillin binding And Serine/Threonine kinase Associated (PASTA) proteins, can sensitize the bacteria to beta-lactam antibiotics. Bacterial Serine/Threonine kinases are signal transducers and our work suggests they are a novel drug development target. While PASTA kinases are common in some gram-positive bacteria, we found there is drug selectivity, not only between human and bacterial kinases, but also between bacterial kinases. We are targeting the subset of PASTA kinase containing bacteria with a large back pocket. We have already obtained a crystal structure of our target bacterial kinase (PknB) with a lead compound demonstrating this pocket. This information enables us to specifically modify the lead to both increase potency and maximize selectivity using previously defined structure activity relationships with human kinases. Furthermore, our atomic resolution drug: target structure will guide us on regions of the drug that can be modified to explicitly test Lipinski's rules for drug development and determine if they should be modified for antibiotic drug development. In this proposal, we will build on our existing work with the following Specific Aims: Aim 1: Design, synthesize, and test both biochemically and microbiologically novel aminofurazan kinase inhibitors that exploit the uniquely shaped back pocket of some of the PknB family of kinases. Aim 2: Test the toxicity of these novel kinase inhibitors, as well as determine the effectiveness of combined beta lactam antibiotics with kinase inhibition in an animal model (Danio rerio). We will analyze the effect of our kinase inhibitors on both a panel of human kinases as well as on embryogenesis and fertility in zebrafish. When this work is complete, we will have generated data on how to design kinase inhibitors that act poorly against human and zebrafish kinases, but are potent against certain bacterial kinases. Pathogens that include kinases with this unique back pocket morphology include diverse skin and soil bacteria that complicate traumatic and surgical infections in the VA such as Clostridia, Nocardia, Propionibacterium acnes, and Mycobacterium. Furthermore, our work will set the stage for early stage trials on treating drug resistant mycobacterial and nocardial infections as well as atypical skin organisms that can complicate surgical infections common in veterans using a novel agent that synergizes with an existing antibiotic class with low toxicity.

抗生素耐药细菌是对人类健康的主要威胁。每年在美国， 大约200万人感染了对抗生素耐药性的细菌，至少导致 23,000人死亡。需要开发新型抗生素。但是，从头抗生素的开发是 资源密集型。鉴于投资回报率差，主要的制药公司显着 减少抗生素研发工作。学术实验室通常无法访问 化合物和足够的基本原理设计数据。接受外科手术程序的退伍军人， 包括头部外伤在内，容易受到多种手术感染的攻击，有时有生物不太可能 代表制药公司的有吸引力的目标。 利用行业进行的现有药物设计工程的抗生素开发可能避免 由于药理学性质不佳而导致的一些昂贵的失误，这些特性可能无意中出现 选择。我们的方法使用基于结构的计算建模来将药物重新利用为抗生素。 我们实验室的先前工作表明，属于青霉素家族的李斯特菌激酶的抑制作用 结合和丝氨酸/苏氨酸激酶相关（面食）蛋白可以使细菌敏感到β-内酰胺 抗生素。细菌丝氨酸/苏氨酸激酶是信号传感器，我们的工作表明它们是一种新颖 药物开发目标。虽然面食激酶在某些革兰氏阳性细菌中很常见，但我们发现有 药物选择性，不仅在人和细菌激酶之间，而且在细菌激酶之间。我们是 靶向含有大后袋细菌的面食激酶的子集。我们已经获得了 我们的靶细菌激酶（PKNB）的晶体结构，带有铅化合物，证明了该口袋。这 信息使我们能够专门修改引线以提高效力并最大程度地提高选择性 以前定义的结构活动与人类激酶的关系。此外，我们的原子分辨率药物： 目标结构将指导我们进行可以修改的药物区域，以明确测试Lipinski的规则 药物开发并确定是否应修改它们以进行抗生素药物开发。在此提案中， 我们将以以下特定目标在现有工作的基础上进行： AIM 1：设计，合成和测试生化和微生物学新颖的氨基轮 激酶抑制剂可利用某些PKNB激酶家族的独特形状后袋。 目标2：测试这些新型激酶抑制剂的毒性，并确定 在动物模型（Danio rerio）中，将β乳糖抗生素与激酶抑制结合在一起。我们将 分析我们的激酶抑制剂对人类激酶和对人群的影响 斑马鱼中的胚胎发生和生育能力。 完成这项工作后，我们将生成有关如何设计激酶抑制剂的数据 反对人和斑马鱼激酶，但对某些细菌激酶有效。包括病原体 具有这种独特的后袋形态的激酶包括复杂的皮肤和土壤细菌 VA中的创伤性和外科感染，例如梭状芽胞杆菌，诺卡氏菌，丙酸杆菌和 分枝杆菌。此外，我们的工作将为治疗耐药性的早期试验奠定基础 分枝杆菌和多心脏感染以及非典型皮肤生物，使手术复杂化 在退伍军人中使用的新型药物在退伍军人中常见的感染，该新药物与现有的抗生素类协同作用 毒性。