The quinazolinone class of antibacterial agents

喹唑啉酮类抗菌剂

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：金黄色葡萄球菌是在人体和皮肤潮湿区域中发现的一种常见细菌。大约有29％的美国人口与金黄色葡萄球菌在鼻子中殖民，其中1.5％是耐甲氧西林的金黄色葡萄球菌（MRSA）。每年，美国有278,000人患有MRSA感染，导致19,000人死亡。 MRSA的传播也在社区获得的感染中发现，美国MRSA每年每年都有超过600万个门诊就诊。多年来，β-内酰胺是金黄色葡萄球菌感染治疗的抗生素。但是，这些药物在MRSA的出现时面临过时。我们发现了喹唑酮类抗菌剂，它们暴露了针对MRSA的活性，包括难以治疗的万古霉素和耐二唑霉素的MRSA菌株。二唑啉酮在感染动物模型中显示出效率，并且在小鼠中具有口服生物利用度。喹唑啉酮具有抗菌活性，但它们也与β-内酰胺抗生素协同作用。我们已经表明，喹唑啉酮与青霉素结合蛋白2a（PBP2A）中的变构位点结合，这是一种前所未有的任何抗菌作用方式。与活性位点的变构位点触发的结合，这是一种独特的机制，也可以通过与ß-内酰胺抗生素共同给药来探索以使PBP2A失活，从而恢复了MRSA的过时β-内酰胺抗生素I治疗。提出了三个特定的目的，以优化喹唑啉酮类抗生素。这些研究包括其他作用实验的机理，药效学，耐药的出现研究以及对喹唑啉酮与其他抗生素的组合的评估。研究将绘制临床前的图表这些新型抗生素的开发在包括MRSA在内的革兰氏阳性细菌治疗感染方面有望。