The quinazolinone class of antibacterial agents

喹唑啉酮类抗菌剂

• 批准号: 9222697
• 负责人: Mayland F Chang
• 金额: $ 60.2万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-20 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222697
• 关键词: Accounting; Active Sites; Allosteric Site; Animal Model; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Applications Grants; Area; Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Binding Proteins; Biological Assay; Biological Availability; Carbapenems; Cephalosporins; Cessation of life; Community-Acquired Infections; Complex; Computer Simulation; Digital Libraries; Docking; Drug Interactions; Drug resistance; Evaluation; Exhibits; Goals; Gram-Positive Bacteria; Human; Human body; In Vitro; Infection; Investigation; Laboratories; Lead; Libraries; Linezolid; Metabolic; Methicillin Resistance; Methods; Molecular Conformation; Monobactams; Mus; Nose; Oral; Outpatients; Penicillin-Binding Proteins; Penicillins; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Plasma Proteins; Population; Property; Rattus; Resistance; Scheme; Site; Skin; Staphylococcus aureus; Structure; Toxic effect; Vancomycin; Visit; Wit; Work; X-Ray Crystallography; beta-Lactams; combinatorial; design; drug resistant bacteria; experimental study; fighting; improved; in vivo; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; novel; preclinical development; public health relevance; resistance mechanism; resistant strain; synergism; water solubility

 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.

 描述（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% 的美国人鼻腔内定植有金黄色葡萄球菌，其中 1.5% 为耐甲氧西林金黄色葡萄球菌 (MRSA)。美国每年有 278,000 人因 MRSA 感染而住院，导致 19,000 人死亡。 MRSA 的传播也存在于社区获得性感染中，美国每年有超过 600 万人次的门诊就诊是由 MRSA 引起的。多年来，β-内酰胺类药物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，这些药物面临着淘汰。我们发现了喹唑啉酮类抗菌剂，对 MRSA 具有活性，包括难以治疗的万古霉素和利奈唑胺耐药 MRSA 菌株。喹唑啉酮先导药物在感染动物模型中显示出功效，并且在小鼠中具有口服生物利用度。喹唑啉酮类化合物本身具有抗菌活性，但它们也与 β-内酰胺类抗生素具有协同作用。我们已经证明喹唑啉酮类药物与青霉素结合蛋白 2a (PBP2a) 的变构位点结合，这是任何抗菌药物前所未有的作用模式。与变构位点的结合触发活性位点的打开，这是一种独特的机制，也可用于通过与 β-内酰胺抗生素共同给药来灭活 PBP2a，从而在治疗 MRSA 时复活过时的 β-内酰胺抗生素。提出了喹唑啉酮类抗生素先导化合物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、耐药性出现的研究以及喹唑啉酮类药物与其他抗生素组合的评估。这些研究将绘制临床前 这些新型抗生素的开发有望治疗包括 MRSA 在内的革兰氏阳性菌感染。