Discovery of a New Class of Antibacterials that Inhibits Penicillin-Binding Proteins

发现一类抑制青霉素结合蛋白的新型抗菌药

• 批准号: 8836124
• 负责人: Renee Bouley
• 金额: $ 4.31万
• 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: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836124
• 关键词: Active Sites; Allosteric Site; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacterial Infections; Binding; Biochemistry; Biological Availability; Cefepime; Cell Wall; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Combined Modality Therapy; Community-Acquired Infections; Complex; Crystallization; Daptomycin; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Enzymes; Genes; Goals; Hand; Hospitals; In Vitro; Infection; Investigation; Knowledge; Lactams; Lead; Linezolid; Marketing; Methods; Microbiology; Modeling; Monobactams; Mus; Oral; Organic Synthesis; Oxacillin; Penetration; Penicillin-Binding Proteins; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Proteins; Public Health; Reporting; Resistance; Serine; Site; Site-Directed Mutagenesis; Staphylococcus aureus; Structure; Structure-Activity Relationship; Testing; Toxic effect; Treatment outcome; United States; Vancomycin; Virulent; Water; analog; design; disorder prevention; expression vector; improved; in vivo; intravenous administration; methicillin resistant Staphylococcus aureus; mouse model; mutant; pathogen; public health relevance; resistant strain; structural biology; synergism

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.

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 已被疾病控制和预防中心认定为对公共健康的严重威胁。市场上的许多抗生素不再有效治疗 MRSA 感染，仅在美国每年就会导致超过 11,000 人死亡。目前批准用于治疗MRSA感染的抗生素有万古霉素、利奈唑胺、头孢洛林和达托霉素，其中只有利奈唑胺可以口服。此外，所有四种已批准药物均已显示出耐药性。这强调了开发能够有效治疗这些细菌感染的新型口服抗生素的重要性。 我们发现了一类新的抗菌剂——喹唑啉酮类药物，它对 MRSA 感染的小鼠模型有效，并描述了其作用机制。喹唑啉酮铅为水溶性，口服生物利用度好，清除率低，无毒；然而，它的分布量不大。喹唑啉酮与青霉素结合蛋白 (PBP) 2a（一种参与细胞壁合成的酶）的变构位点结合，并触发活性位点的打开。本提案旨在对喹唑啉酮类药物进行先导化合物优化，研究喹唑啉酮类药物与其他抗生素的协同作用，并进一步研究喹唑啉酮类药物的作用机制。该提案是一个跨学科项目，涉及有机合成、生物化学、微生物学、结构生物学、药理学和感染动物模型。这些研究将扩展我们在设计有效的抗 MRSA 化合物和了解这类新型抗菌药物方面的知识。