The quinazolinone class of antibacterial agents

 描述（由申请人提供）：金黄色葡萄球菌是一种常见于人体和皮肤潮湿区域的细菌。大约29%的美国人的鼻子中有S。金黄色葡萄球菌中耐甲氧西林的占1.5%。金黄色葡萄球菌（MRSA）。美国每年有27.8万人因MRSA感染住院，导致1.9万人死亡。MRSA的传播也存在于社区获得性感染中，在美国每年有超过600万的门诊就诊由MRSA引起。多年来，β-内酰胺类抗生素是治疗S.金黄色葡萄球菌感染然而，随着MRSA的出现，这些药物面临淘汰。我们已经发现了喹唑啉酮类抗菌剂，其对MRSA表现出活性，包括难以治疗的万古霉素和利奈唑胺耐药MRSA菌株。喹唑啉酮铅在动物感染模型中显示出有效性，并且在小鼠中具有口服生物利用度。喹唑啉酮本身具有抗菌活性，但它们也与β-内酰胺抗生素协同作用。我们已经证明，喹唑啉酮结合到青霉素结合蛋白2a（PBP 2a）的变构位点，这是任何抗菌剂前所未有的作用模式。与变构位点的结合触发活性位点的开放，这是一种独特的机制，也可以通过与β-内酰胺抗生素共同施用来利用其抑制PBP 2a，从而在MRSA的治疗中恢复废弃的β-内酰胺抗生素。提出了喹唑啉酮类抗生素先导优化的三个具体目标。这些研究包括额外的作用机制实验、药效学、耐药性出现的调查以及喹唑啉酮与其他抗生素组合的评价。这些研究将绘制临床前 这些新型抗生素的开发，有望治疗革兰氏阳性菌感染，包括MRSA。

 DESCRIPTION (provided by applicant): Staphylococcus aureus is a common bacterium found in moist areas of the human body and skin. Approximately 29% of the US population is colonized in the nose with S. aureus, of which 1.5% is methicillin- resistant S. aureus (MRSA). Annually, 278,000 people in the US are hospitalized with MRSA infections, resulting in 19,000 deaths. Spread of MRSA is also found in community-acquired infections, with over 6 million outpatient visits every year in the US caused by MRSA. Over the years, ß-lactams were antibiotics of choice in treatment of S. aureus infections. However, these agents faced obsolescence with the emergence of MRSA. We have discovered the quinazolinone class of antibacterial agents, which exhibit activity against MRSA, including hard-to-treat vancomycin- and linezolid-resistant MRSA strains. The lead quinazolinone shows efficacy in animal models of infection and has oral bioavailability in mice. The quinazolinones have antibacterial activity o their own, but they also synergize with ß-lactam antibiotics. We have shown that the quinazolinones bind to the allosteric site in penicillin-binding protein 2a (PBP2a), an unprecedented mode of action for any antibacterial. The binding to the allosteric site triggers opening of the active site, a unique mechanism that can also be exploited to inactivate PBP2a by co-administration with ß-lactam antibiotics, thus resurrecting obsolete ß-lactam antibiotics i treatment of MRSA. Three Specific Aims are proposed for lead optimization of the quinazolinone class of antibiotics. These studies include additional mechanism of action experiments, pharmacodynamics, investigation of emergence of resistance, and evaluation of combinations of the quinazolinones with other antibiotics. These studies will chart the preclinical development of these novel antibiotics, which hold promise in treatment of infections by Gram-positive bacteria, including MRSA.