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）患者预后较差，三分之一的患者在一年内死于感染。心内膜炎的治疗包括抗生素治疗和/或手术，每位患者的费用高达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。对抗生素治疗无效的心内膜炎病例通常是由耐药生物引起的，特别是耐甲氧西林金黄色葡萄球菌（MRSA）。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的技术不是作为细菌的杀微生物剂，而是抑制抗生素的防御机制，从而使耐药菌株对传统的抗生素治疗变得敏感。敏捷科学的联合创始人，dr。北卡罗莱纳州立大学的克里斯蒂安·梅兰德和约翰·卡瓦纳已经开发出一类新的2-氨基咪唑（2-AI）小分子，可以与细菌内的一种新的蛋白质目标结合。这些2-AI分子抑制细菌对环境刺激（包括抗生素）的反应能力，从而使细菌对抗生素更敏感。Agile Sciences的2-AI化合物已被证明可以降低抗MRSA的细胞壁作用抗生素的MIC，并且这类新型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药物评估的有希望的支架。

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.