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

描述（由申请人提供）：感染性心内膜炎（IE）患者预后不良，三分之一的患者在第一年内死于感染。心内膜炎的治疗涉及抗生素治疗和/或手术，每位患者的费用超过10万美元;然而，许多病例对抗生素治疗没有反应，手术风险很高。抗生素治疗无效的心内膜炎病例通常由耐药生物体，特别是耐甲氧西林金黄色葡萄球菌（MRSA）引起。Agile Sciences正在开发一种治疗耐药细菌感染的替代方法，该方法绕过了开发新抗生素的许多固有限制。Agile Sciences的技术并不作为细菌的杀微生物剂，而是抑制抗生素防御机制，使耐药菌株对传统抗生素疗法敏感。敏捷科学的联合创始人，北卡罗来纳州州立大学的Christian Melander和John Cavanagh博士开发了一类新的2-氨基咪唑（2-AI）小分子，可以与细菌内的一种新蛋白质靶点结合。这些2-AI分子抑制细菌对包括抗生素在内的环境刺激做出反应的能力，从而使细菌对抗生素更加敏感。敏捷科学公司的2-AI化合物已被证明可以降低细胞壁作用抗生素对MRSA的MIC，这种新型的2-AI化合物还可以抑制和分散MRSA生物膜。初步研究表明，这些2-AI化合物具有良好的毒性和代谢稳定性，因此它们代表了作为潜在治疗剂进行评估的有希望的支架。 该提案的总体目标是获得概念证明，即敏捷科学公司的2-AI化合物在IE的体内模型中增强了对MRSA的抗生素功效。目标1的目的是使用生物活性、毒性和药代动力学特性的评估对先导化合物进行排序。在目标2中，将在完善的IE大鼠模型中评价最有前途的2-AI化合物作为抗生素辅助治疗的体内有效性。该项目将由Angela Pollard博士监督，他是一位微生物学家，在微生物定植和宿主-病原体相互作用方面具有专业知识。体内模型将由Yan Xiong博士领导的经验丰富的UCLA科学家团队执行，并由着名的心内膜炎模型专家Arnold Bayer博士提供咨询专业知识。杜克大学的Ralph Corey医生将为该项目提供宝贵的临床见解。 如果Agile Sciences的2-AI化合物在IE的体内模型中成功地增强了当前抗生素对MRSA的活性，那么这类新的分子可能会为治疗目前对治疗有抗药性的IE感染提供更有效的治疗策略。由于这种改进的疗法，治疗的高成本和风险降低了。 手术以及与这种疾病相关的高死亡率可能是 大幅减少。

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.