Small Molecule Antibiotic Potentiators for Drug-Resistant Bacteria

针对耐药细菌的小分子抗生素增效剂

• 批准号: 9039744
• 负责人: DAVID JUNG
• 金额: $ 29.43万
• 依托单位: AGILE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039744
• 关键词: Acinetobacter baumannii; Address; Affinity; American; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Binding; Binding Proteins; Biological Assay; Cell Signaling Process; Cell Wall; Cessation of life; Clinical; Clinical Trials; Combined Antibiotics; Combined Modality Therapy; Consult; Defense Mechanisms; Drug resistance; Economic Burden; Economics; Effectiveness; Enterobacter; Enterococcus faecium; Environment; Evaluation; Goals; Gram-Negative Bacteria; Head; Health Care Costs; Hospitals; Infection; Klebsiella pneumonia bacterium; Lead; Ligands; Lipid A; Measures; Metabolic; Minimum Inhibitory Concentration measurement; Modification; Multi-Drug Resistance; OmpR protein; Patients; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Plasma Proteins; Pneumonia; Program Development; Property; Pseudomonas aeruginosa; Public Health; Reporter; Research; Resistance; Safety; Science; Spectrometry, Mass, Electrospray Ionization; Staphylococcus aureus; Stimulus; Surface Plasmon Resonance; System; Technology; Therapeutic; Toxic effect; Universities; Urinary tract infection; Wound Infection; bacterial resistance; combat; cytotoxicity; design; drug development; drug resistant bacteria; effective therapy; exhaust; experience; improved; in vivo; inhibitor/antagonist; interest; meetings; methicillin resistant Staphylococcus aureus; novel; novel therapeutics; pathogen; programs; public health relevance; repaired; resistance mechanism; resistant strain; response; scaffold; signal processing; small molecule; therapeutic target; tool

 DESCRIPTION (provided by applicant): An estimated two million Americans suffer from infections caused by multi-drug resistant (MDR) bacteria resulting in a substantial impact on patients' lives and an extraordinary economic burden. Due to the arsenal of antibiotic resistance mechanisms that these bacteria present, traditional antibiotic therapies are often ineffective. New strategies that use a novel mechanism of action are needed to augment the arsenal of therapeutic options to address the growing problem of MDR bacteria. Agile Sciences' co-founders, Drs. Christian Melander and John Cavanagh of NC State University, have developed a new class of 2- aminoimidazole (2-AI) small molecules that act via a novel mode of action to inhibit the ability of the bacteria to respond to environmental stimuli, thus rendering the bacteri more sensitive to antibiotics. The 2-AI molecules inhibit response regulator (RR) proteins of two-component systems resulting in lower antibiotic MIC values against MDR strains of Gram-positive and Gram-negative bacteria. In addition, the 2-AI compounds have favorable toxicity and metabolic stability profiles, and so they represent promising scaffolds for evaluation as potential therapeutics to address problems associated with MDR bacteria. The overarching goal of this proposal is to identify lead 2-AI molecules against each of three target bacteria (methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa) that substantially increase the efficacy of antibiotics and have pharmaceutically relevant attributes. RR proteins are an untapped target; therefore, there are insufficient tools fo target binding studies. For this reason, the objective of Aim 1 is to generate target binding assays against three RR proteins that have been implicated in antibiotic resistance (S. aureus VraR, A. baumannii PmrA, and P. aeruginosa CzcR). These binding assays, involving electrospray ionization mass spectrometry, surface plasmon resonance, and reporter strains, will be used to direct medicinal chemistry efforts in Aim 2. In addition to target binding, 2-AI derivatives synthesized in Aim 2 will be evaluated for MIC-lowering, cytotoxicity, metabolic stability, and plasma protein binding properties. This project will be overseen by Dr. Angela Pollard, Agile Sciences' Director of Research, who has successfully managed development programs at Agile Sciences. Dr. Cavanagh, an expert in bacterial cell signaling processes, will design and validate RR protein binding assays in Aim 1. Dr. David Jung, a medicinal chemist with 20 years of experience, and Dr. Steve Young, former head of Medicinal Chemistry at Merck, will be responsible for designing 2-AI derivatives in Aim 2. Dr. Jeff Collins, who has over 30 years of drug development experience specializing in anti-infectives, will provide consulting expertise. This project has the potential to significantly impact the field of antibiotic drug development. This new strategy for disabling bacterial resistance mechanisms could lead to a novel therapeutic that will provide clinicians with an effective treatment option for infection caused by MDR bacterial pathogens.

 描述（由申请人提供）：估计有200万美国人患有由多药耐药（MDR）细菌引起的感染，对患者的生活产生重大影响，并造成巨大的经济负担。由于这些细菌存在大量的抗生素耐药机制，传统的抗生素治疗往往无效。需要使用新的作用机制的新策略来增加治疗选择的武库，以解决日益严重的MDR细菌问题。敏捷科学的联合创始人，北卡罗来纳州立大学的Christian Melander和John Cavanagh博士开发了一类新的2-氨基咪唑（2-AI）小分子，通过一种新的作用模式来抑制细菌对环境刺激的反应能力，从而使细菌对抗生素更加敏感。2-AI分子抑制双组分系统的反应调节（RR）蛋白，导致针对革兰氏阳性和革兰氏阴性细菌的MDR菌株的较低抗生素MIC值。此外，2-AI化合物具有良好的毒性和代谢稳定性，因此它们代表了有希望的支架，可作为潜在的治疗剂用于评估，以解决与MDR细菌相关的问题。 该提案的总体目标是确定针对三种靶细菌（耐甲氧西林金黄色葡萄球菌、鲍曼不动杆菌和铜绿假单胞菌）中每一种的铅2-AI分子，这些分子可显著提高抗生素的疗效并具有药学相关属性。RR蛋白是一个未开发的靶点，因此，没有足够的工具进行靶点结合研究。出于这个原因，目的1的目的是产生针对三种与抗生素耐药性有关的RR蛋白的靶向结合测定（S. aureus VraR、A.鲍曼不动杆菌PmrA和铜绿假单胞菌CzcR）。这些结合试验，包括电喷雾电离质谱，表面等离子体共振，和报告菌株，将用于指导目标2中的药物化学工作。除了靶点结合外，还将评价目标2中合成的2-AI衍生物的MIC降低、细胞毒性、代谢稳定性和血浆蛋白结合特性。该项目将由敏捷科学研究总监Angela Pollard博士监督，他成功地管理了敏捷科学的开发项目。Cavanagh博士是细菌细胞信号传导过程的专家，他将在Aim 1中设计和验证RR蛋白结合试验。拥有20年经验的药物化学家大卫荣格博士和默克公司药物化学前负责人史蒂夫杨博士将负责设计Aim 2中的2-AI衍生物。杰夫柯林斯博士，谁拥有超过30年的药物开发经验，专门从事抗感染，将提供咨询专业知识。 该项目有可能对抗生素药物开发领域产生重大影响。这种禁用细菌耐药机制的新策略可能会导致一种新的治疗方法，为临床医生提供一种有效的治疗选择，用于治疗MDR细菌病原体引起的感染。