Evaluation of a new class of molecules for treating MRSA infective endocarditis

治疗 MRSA 感染性心内膜炎的一类新分子的评价

• 批准号: 8521011
• 负责人: Angela Marie Pollard
• 金额: $ 30万
• 依托单位: AGILE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521011
• 关键词: Adjuvant; Adjuvant Therapy; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Binding; Biological; Bypass; Cell Wall; Charge; Chemicals; Clinical; Consult; Defense Mechanisms; Development; Diagnosis; Disease; Disease Outcome; Dose; Drug Kinetics; Drug resistance; Effectiveness; Endocarditis; Ensure; Environment; Evaluation; Goals; In Vitro; Incidence; Infection; Infective endocarditis; Lead; Length of Stay; Maximum Tolerated Dose; Measures; Medical; Metabolic; Microbial Biofilms; Modeling; Mus; North Carolina; Nosocomial Infections; OmpR protein; Operative Surgical Procedures; Organism; Oxacillin; Patients; Penicillin-Binding Proteins; Permeability; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Physicians; Property; Proteins; Rattus; Regimen; Resistance; Risk; Science; Scientist; Signal Transduction; Small Business Technology Transfer Research; Stimulus; System; Technology; Testing; Therapeutic; Toxic effect; Universities; base; cost; cytotoxicity; efficacy testing; expectation; experience; high risk; improved; in vitro Assay; in vivo; in vivo Model; insight; intraperitoneal; meetings; methicillin resistant Staphylococcus aureus; microbial colonization; microbial host; microbicide; mortality; novel; outcome forecast; pathogen; public health relevance; resistance mechanism; resistant strain; scaffold; small molecule; therapy development

DESCRIPTION (provided by applicant): Patients with infective endocarditis (IE) have a poor prognosis with one third of the patients succumbing to the infection within the first year. Treatments for endocarditis involve antibiotic therapy and/or surgery that cost upwards of $100,000 per patient; however, many cases do not respond to the antibiotic treatment and surgery poses high risks. Cases of endocarditis that are recalcitrant to antibiotic therapies are often caused by drug- resistant organisms, in particular methicillin-resistant Staphylococcus aureus (MRSA). Agile Sciences is developing an alternative approach to treating resistant bacterial infections that bypasses many of the inherent limitations of developing new antibiotics. Agile Sciences' technology does not act as a microbicide to the bacteria, but instead inhibits antibiotic defense mechanisms, so that resistant strains become susceptible to traditional antibiotic therapies. Agile Sciences' co-founders, Drs. Christian Melander and John Cavanagh of North Carolina State University, have developed a new class of 2-aminoimidazole (2-AI) small molecules that bind to a novel protein target within the bacteria. These 2-AI molecules inhibit the ability of the bacteria to respond to environmental stimuli, including antibiotics, thu rendering the bacteria more sensitive to antibiotics. Agile Sciences' 2-AI compounds have been shown to lower the MIC of cell wall-acting antibiotics against MRSA, and this novel class of 2-AI compounds also inhibits and disperses MRSA biofilms. Preliminary studies indicate that these 2-AI compounds have favorable toxicity and metabolic stability profiles, and so they represent promising scaffolds for evaluation as potential therapeutics. The overarching goal of this proposal is to obtain proof of concept that Agile Sciences' 2-AI compounds enhance antibiotic efficacy against MRSA in an in vivo model of IE. The objective of Aim 1 is to rank lead compounds using assessments of biological activity, toxicity, and pharmacokinetic properties. In Aim 2, the most promising 2-AI compound will be evaluated for in vivo effectiveness as an antibiotic adjuvant therapy in a well-established rat model of IE. This project will be overseen by Dr. Angela Pollard, a microbiologist with expertise in microbial colonization and host-pathogen interactions. The in vivo model will be executed by an experienced team of UCLA scientists led by Dr. Yan Xiong, with consulting expertise by Dr. Arnold Bayer, a well-known expert in endocarditis models. Physician Dr. Ralph Corey of Duke University will contribute valuable clinical insight to this project. If Agile Sciences' 2-AI compounds are successfully shown to enhance the activity of current antibiotics against MRSA in an in vivo model of IE, this new class of molecules could potentially provide a more effective therapeutic strategy for treating IE infections that are currently resistant to treatment. As a result of this improved therapy, the high costs and risks of surgery as well as the substantial mortality rate associated with this disease could potentially be significantly reduced.

描述（由申请人提供）：感染性心内膜炎患者（IE）的预后较差，三分之一的患者在第一年内屈服于感染。心内膜炎的治疗涉及抗生素疗法和/或手术，每位患者的费用超过100,000美元；但是，许多病例对抗生素治疗和手术没有反应会带来高风险。对抗生素疗法的顽固性心内膜炎病例通常是由抵抗药物的生物，特别是耐甲氧西林金黄色葡萄球菌（MRSA）引起的。敏捷科学正在开发一种治疗抗性细菌感染的替代方法，该方法绕过了发展新抗生素的许多固有局限性。敏捷科学的技术不充当细菌的杀菌剂，而是抑制抗生素防御机制，因此抗性菌株变得容易受到传统的抗生素疗法的影响。敏捷科学的联合创始人，博士。北卡罗来纳州立大学的克里斯蒂安·梅兰德（Christian Melander）和约翰·卡瓦纳（John Cavanagh）开发了一种新的2-氨基咪唑（2-ai）小分子，这些分子与细菌内的新型蛋白质靶标结合。这些2-AI分子抑制细菌对环境刺激的反应能力，包括抗生素，使细菌对抗生素更敏感。敏捷科学的2-AI化合物已被证明可以降低针对MRSA的细胞壁作用抗生素的MIC，而这种新型的2-AI化合物也抑制MRSA生物膜。初步研究表明，这些2-AI化合物具有有利的毒性和代谢稳定性，因此它们代表了有希望的脚手架作为潜在疗法的评估。 该提案的总体目的是获得概念证明，即敏捷科学的2-AI化合物在IE的体内模型中增强了对MRSA的抗生素疗效。目标1的目的是使用评估生物活性，毒性和药代动力学特性对铅化合物进行排名。在AIM 2中，将评估最有希望的2-AI化合物在IE的大鼠模型中作为一种抗生素辅助治疗的体内有效性。该项目将由具有微生物定植和宿主 - 病原体相互作用方面的专业知识的微生物学家Angela Pollard博士监督。体内模型将由经验丰富的UCLA科学家团队执行，由Yan Xiong博士领导，并由心内膜炎模型著名专家Arnold Bayer博士咨询专业知识。杜克大学的医师Ralph Corey博士将为该项目提供宝贵的临床见解。 如果成功证明了敏捷科学的2-AI化合物在IE的体内模型中增强当前抗生素对MRSA的活性，则这种新的分子可能会提供更有效的治疗策略，以治疗当前抗治疗的IE感染。由于这种改进的治疗，高成本和风险 手术以及与这种疾病相关的实质死亡率可能可能是 大幅减少。