Compound and Strategies for Treating MRSA and VRE

OJECT摘要(请参阅说明)： 具有抗生素耐药性的细菌感染已成为世界范围内的一个主要问题。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(VRE)感染是特别危险的。这项提议是哈佛大学计划的一个子项目，目的是解决开发新方法来克服这些感染的必要性。这一分项目的四个目标是探索新的化合物、目标和战略，以克服耐甲氧西林金黄色葡萄球菌和VRE。第一个目标是开发化学和酶相结合的方法来制造新型的磷脂抗生素，通过靶向制造肽聚糖(PG)糖链的酶来抑制PG的生物合成。第二个目的是阐明粪肠球菌合成壁磷壁酸(WTA)的途径，并评估其作为抗菌靶标的潜力，为抑制剂的筛选奠定基础。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。第四个目标将与其他子项目合作实施，目的是评估我们在优先动物模型中发现的化合物。 这些研究将包括对我们之前发现的、已经优化了体外活性的一种8.金黄色选择WTA活性抗生素的评估。这项拟议的研究可能会导致开发新的抗生素，用于临床治疗MRSA和VRE感染。

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.