Harvard-wide Program on Antibiotic Resistance

PPG描述(由申请人提供)：MRSA是严重侵袭性感染和死亡的主要原因。随着VRE(多药耐药医院感染的主要原因)对万古霉素的耐药性的引入，这一问题变得迫切起来。PPG的主题是“基于新的复合筛选和对抗生素耐药性的发展、生理和传播的理解，抗击MRSA和VRE感染的新方法。”PPG的目标是通过向开发管道提供10种有效的化合物来治疗这些感染，从而改变治疗模式，同时在基础科学方面取得重大进展。跨学科团队将采取创新的学术方法，包括创造性的新屏幕和基于信息的化合物鉴定，以及对抗生素耐药性及其传播的分子生物学的高级理解。这种合作伙伴关系拥有高通量筛查/跟踪化学、生物化学、分子生物学、分子遗传学、分子发病机制和临床微生物学方面的专业知识，带来了横跨哈佛大学-麻省理工学院、麻省理工学院、哈佛大学和麻省理工学院的机构的视角和资产。眼耳医务室--不负责任。所有项目负责人都是各自领域的领导者，由一支具有非凡的科学广度和成就以及管理经验的团队组成。协同效应使第一年取得了重大进展。在Walker项目中产生了用于抑制MRSA WTA合成的最初的先导和第二个优化的结构。与Gilmore小组合作，这些化合物被证明在哺乳动物组织中有效，无毒，对MSSA和MRSA临床分离株的MIC较低；此外，WTA缺陷菌株对刚果红和其他偶氮化合物极其敏感，因此设计了拟议时期的新筛查。与Mylonakis/Ausubel和Hooper小组的合作表明，WTA缺陷的金黄色葡萄球菌可以分别在线虫和小鼠模型中用b-内酰胺类药物成功治疗。这一系列研究贯穿了所有的研究小组，第二代WTA抑制剂现在正在NIH的临床前开发流水线中推进。 相关性：三个项目采用独立、创新和最先进的方法来确定用于治疗MRSA、VRE和VRSA感染的先导化合物，并扩大支持其活动的知识库。另外两个项目在体外和体内测试这些化合物，并确定它们与抗生素耐药性和耐药性传播的关系。一种化合物已经得到验证，该项目的目标是在推进相关科学的同时，再提供10种化合物

DESCRIPTION OF THE PPG (provided by the applicant): MRSA is a leading cause of severe invasive infection and mortality. This has become urgent with the introduction of vancomycin resistance from VRE (leading causes of multidrug resistant hospital infection). The PPG theme is "New approaches for combating MRSA and VRE infection based on novel compound screens and an understanding of development, physiology, and spread of antibiotic resistance." The PPG aims to shift treatment paradigms by providing to development pipelines as deliverables, 10 validated compounds for treating these infections ~ while simultaneously making significant advances to the underlying science. The interdisciplinary team will take an innovative academic approach that involves creative new screens and information-based compound identification, coupled with an advanced understanding of the molecular biology of antibiotic resistance and its transmission. This collaborative partnership, with expertise in high throughput screening/follow up chemistry, biochemistry, molecular biology, molecular genetics, molecular pathogenesis, and clinical microbiology, brings the perspectives and assets of institutions spanning Harvard University- MGH, HMS, Harvard College, and Mass. Eye and Ear Infirmary - to bear. All Project Leaders are leaders in their respective fields, comprising a team of unusual scientific breadth and accomplishment, and administrative experience. Synergy allowed significant advances to be made in the first year. An initial lead and a second, optimized structure for inhibiting MRSA WTA synthesis were generated in the Walker project. Working with the Gilmore group, these compounds were shown to be effective in mammalian tissues, to be non-toxic, and to have low MICs for clinical isolates of MSSA and MRSA; moreover, WTA deficient strains were extremely sensitive to Congo Red and other azo compounds, leading to the design of new screens for the proposed period. Collaborative work with the Mylonakis/Ausubel and Hooper groups showed that WTA defective S. aureus could be successfully treated with b-lactams in C. elegans and murine models respectively. This one line of investigation ran through all groups, and the 2nd generation WTA inhibitor is now advancing through the NIH preclinical development pipeline. RELEVANCE: Three projects take independent, innovative, and state-of-the-art approaches for identifying lead compounds for treating MRSA, VRE and VRSA infection, and expanding the knowledge base that underlies their activity. Two additional projects test these compounds in vitro and in vivo, and determine their relationship to antibiotic resistance and resistance transmission. One compound already has been validated, and the goal of this program is to deliver 10 more along with advancing the attendant science