Compound and Strategies for Treating MRSA and VRE

治疗 MRSA 和 VRE 的化合物和策略

• 批准号: 8376868
• 负责人: Suzanne Walker
• 金额: $ 40.71万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376868
• 关键词: Address; Anabolism; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Attention; Bacterial Infections; Chemicals; Clinical; Collaborations; Communities; Development; Enterococcus faecalis; Enzymes; Evaluation; Genes; Hospitals; Infection; Instruction; Lead; Methods; Morbidity - disease rate; Pathway interactions; Peptidoglycan; Polysaccharides; Research; Resistance; Screening procedure; Taro Vegetable; Teichoic Acids; Vancomycin; Vancomycin Resistance; Work; beta-Lactams; in vitro activity; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; mortality; novel; novel strategies; pathogen; programs

OJECT SUMMARY (See instructions): Antibiotic resistant bacterial infections have become a major problem worldwide. Among Gram positive pathogens, invasive methicillin-resistant Staphylococcus aureus infections (MRSA) and vancomycinresistant enterococcal (VRE) infections represent particular threats. This proposal is a subproject in a Harvard-wide program to address the need to develop new approaches to overcome these infections. The four aims in this subproject are directed towards exploring new compounds, targets, and strategies to overcome MRSA and VRE. The first aim is to develop combined chemical and enzymatic methods to make novel phosphoglycolipid antibiotics that inhibit peptidoglycan (PG) biosynthesis by targeting the enzymes that make the glycan chains of PG. The second aim is to elucidate the pathway for wall teichoic acid (WTA) biosynthesis in Enterococcus faecalis and assess its potential as an antibacterial target in order to lay the groundwork for inhibitor screening. The third aim is to discover novel TarO inhibitors that can be used in combination with beta lactams to overcome MRSA infections. The fourth aim, to be carried out in collaboration with other subprojects, is to evaluate the compounds we discover in prioritized animal models. These studies will include evaluation of a 8. aureus-selective WTA-active antibiotic that we previously discovered and have already optimized for in vitro activity. The proposed research may lead to the development of new antibiotics for clinical use to treat MRSA and VRE infections.

操作总结（参见说明）： 抗生素耐药性细菌感染已成为世界范围内的主要问题。在革兰氏阳性病原体中，侵袭性耐甲氧西林金黄色葡萄球菌感染（MRSA）和耐万古霉素肠球菌感染（VRE）代表了特别的威胁。该提案是哈佛大学范围内的一个项目的子项目，旨在解决开发新方法来克服这些感染的需求。该子项目的四个目标是探索新的化合物，靶标和策略来克服MRSA和VRE。第一个目的是发展化学和酶法相结合的方法，使新的磷酸糖脂抗生素，抑制肽聚糖（PG）的生物合成的酶为靶点，使聚糖链的PG。第二个目的是阐明壁磷壁酸（WTA）的生物合成途径在粪肠球菌和评估其作为抗菌靶标的潜力，以奠定抑制剂筛选的基础。第三个目标是发现新的TarO抑制剂，可以与β内酰胺类药物联合使用，以克服MRSA感染。第四个目标是与其他子项目合作，评估我们在优先动物模型中发现的化合物。 这些研究将包括评估8。金黄色葡萄球菌选择性WTA活性抗生素，我们以前发现，并已优化体外活性。拟议的研究可能导致开发新的抗生素用于临床治疗MRSA和VRE感染。