Discovery of a New Class of Antibacterials that Inhibits Penicillin-Binding Proteins

描述（由申请人提供）：耐甲氧西林金黄色葡萄球菌（MRSA）是医院和社区获得性感染的主要原因。MRSA已被疾病控制和预防中心确定为对公共卫生的严重威胁。市场上的许多抗生素对治疗MRSA感染不再有效，仅在美国每年就有超过11，000人死亡。目前批准用于治疗MRSA感染的抗生素为万古霉素、利奈唑胺、头孢洛林和达托霉素，其中仅利奈唑胺可口服给药。此外，所有这四种获批药物都有耐药性记录。这强调了开发新的口服抗生素的重要性，这些抗生素可以有效地治疗这些细菌感染。 我们已经发现了一类新的抗菌剂，喹唑啉酮类，这是有效的MRSA感染的小鼠模型，并表征其作用机制。喹唑啉酮铅是水溶性的，具有良好的口服生物利用度，低清除率，并且无毒;然而，它具有适度的分布容积。喹唑啉酮与青霉素结合蛋白（PBP）2a（一种参与细胞壁合成的酶）的变构位点结合，并触发活性位点的开放。该提案旨在进行喹唑啉酮类药物的先导优化，研究喹唑啉酮类药物与其他抗生素之间的协同作用，并进一步研究喹唑啉酮类药物的作用机制。该提案是一个跨学科的项目，涉及有机合成，生物化学，微生物学，结构生物学，药理学和感染的动物模型。这些研究将扩大我们在设计有效的抗MRSA化合物和理解这类新的抗菌药物方面的知识。

DESCRIPTION (provided by applicant): Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital- and community-acquired infections. MRSA has been identified as a serious threat to public health by the Centers for Disease Control and Prevention. Many antibiotics on the market are no longer effective in treating MRSA infections, which results in >11,000 deaths a year in the United States alone. The currently approved antibiotics for treating MRSA infections are vancomycin, linezolid, ceftaroline, and daptomycin, of which only linezolid can be dosed orally. In addition, resistance has been documented for all four of these approved drugs. This underscores the importance to develop new, orally available antibiotics that can effectively treat these bacterial infections. We have discovered a new class of antibacterial agents, the quinazolinones, which are effective in a mouse model of MRSA infection and characterized their mechanism of action. The lead quinazolinone is water soluble, has good oral bioavailability, low clearance, and is not toxic; however it has a modest volume of distribution. The quinazolinone binds to the allosteric site of penicillin-binding protein (PBP) 2a, an enzyme involved in cell-wall synthesis, and triggers opening of the active site. This proposal aims to perform lead optimization of the quinazolinone class, to investigate the synergy between the quinazolinones and other antibiotics, and to further investigate the mechanism of action of the quinazolinones. This proposal is an interdisciplinary project that involves organic synthesis, biochemistry, microbiology, structural biology, pharmacology, and animal models of infection. These studies will expand our knowledge in designing effective anti-MRSA compounds and understanding this new class of antibacterials.