The quinazolinone class of antibacterial agents

 描述(申请人提供)：金黄色葡萄球菌是一种常见的细菌，发现于人体和皮肤潮湿的地方。大约29%的美国人口在鼻部定植金黄色葡萄球菌，其中1.5%是耐甲氧西林金黄色葡萄球菌(MRSA)。每年，美国有27.8万人因感染MRSA而住院，导致1.9万人死亡。在社区获得性感染中也发现了MRSA的传播，在美国，由MRSA引起的门诊就诊人数每年超过600万人次。多年来，β-内酰胺类抗生素一直是治疗金黄色葡萄球菌感染的首选抗生素。然而，随着MRSA的出现，这些药物面临淘汰。我们发现了对耐甲氧西林金黄色葡萄球菌(包括耐万古霉素和利奈唑胺的耐甲氧西林金黄色葡萄球菌)具有抗菌活性的喹唑烷酮类抗菌剂。喹唑烷酮铅在动物感染模型中显示出疗效，并在小鼠中具有口服生物利用度。喹唑烷酮类化合物本身具有抗菌活性，但它们也与β-内酰胺类抗生素有协同作用。我们已经证明，喹唑烷酮类化合物与青霉素结合蛋白2a(PBP2a)中的变构位点结合，这对任何抗菌药都是一种前所未有的作用模式。与变构部位的结合触发活性部位的打开，这是一种独特的机制，也可以通过与内酰胺类抗生素联合给药来灭活PBP2a，从而使过时的内酰胺类抗生素I治疗MRSA死灰复燃。针对喹唑烷酮类抗生素的先导优化提出了三个具体目标。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，以及对喹唑烷酮类药物与其他抗生素的联合使用进行评估。这些研究将绘制临床前 这些新型抗生素的开发，在治疗革兰氏阳性菌感染方面有希望，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.