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（由适用提供）：估计有200万美国人受到由多药耐药（MDR）细菌引起的感染，从而对患者的生活产生了重大影响和特殊的经济负担。由于存在这些细菌的抗生素耐药性机制，因此传统的抗生素疗法通常无效。需要采用新型作用机理的新策略来增加治疗选择的武器库来解决日益增长的MDR细菌问题。敏捷科学的联合创始人，博士。 NC州立大学的Christian Melander和John Cavanagh开发了一种新的2-氨基咪唑唑（2-AI）小分子，这些分子通过新型的作用方式起作用，以抑制细菌对环境刺激的反应能力，从而使细菌对抗生素更敏感。 2-AI分子抑制两组分组系统的响应调节剂（RR）蛋白，从而导致抗生素MIC值较低，以抗革兰氏阳性和革兰氏阴性细菌的MDR菌株。此外，2-AI化合物具有有利的毒性和代谢稳定性谱，因此它们代表了评估的承诺脚手架，作为解决与MDR细菌有关的问题的潜在疗法。该提案的总体目标是确定针对三种靶细菌中每一个的铅2-AI分子。 （耐甲氧西林金黄色葡萄球菌，baumannii和铜绿假单胞菌的铜绿病）显着提高了抗生素的有效性并具有物理相关的属性。 RR蛋白是未开发的靶标；因此，在目标结合研究中没有足够的工具。因此，目标1的目的是生成针对抗生素耐药性暗示的三种RR蛋白的目标结合测定（S. aureus vrar，a。baumanniipmra和P. eruginosa czcr）。这些结合测定法涉及电喷雾电离质谱法，表面等离子体共振和报告菌株，将用于指导AIM 2的药物化学工作。除了目标结合，在目标2中合成的2-AI衍生物还将评估用于降低的，降低的，用于降低，降低的，细胞毒性，氧化毒性，代谢稳定性，分泌性稳定性和platisties comparties and Properties。该项目将由敏捷科学研究总监安吉拉·波拉德（Angela Pollard）博士在海外，他成功地管理了敏捷科学的开发计划。细菌细胞信号过程专家卡瓦纳（Cavanagh）博士将在AIM 1中设计和验证RR蛋白结合测定法1。拥有20年经验的医学化学家David Jung博士，默克默克（Merck）药物化学负责人史蒂夫·扬（Steve Young）将负责在AIM中设计2-AI衍生产品2。该项目有可能显着影响抗生素药物开发领域。这种禁用细菌耐药机制的新策略可能会导致一种新型的治疗性，该治疗方法将为临床医生提供由MDR细菌病原体引起的感染的有效治疗选择。