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已经被疾病控制和预防中心认定为对公众健康的严重威胁。市场上的许多抗生素不再有效治疗MRSA感染，仅在美国，每年就有1000万人死于MRSA感染。目前被批准用于治疗MRSA感染的抗生素有万古霉素、利奈唑胺、头孢他林和达托霉素，其中只有利奈唑胺可以口服。此外，这四种获批药物均有耐药记录。这强调了开发新的口服抗生素以有效治疗这些细菌感染的重要性。

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.