Harvard-wide Program on Antibiotic Resistance

哈佛大学抗生素耐药性计划

• 批准号: 8531132
• 负责人: Frederick M Ausubel
• 金额: $ 202.87万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531132
• 关键词: Abscess; Address; Antibiotic Resistance; Azo Compounds; Biochemistry; Biological Assay; Caenorhabditis elegans; Chemistry; Clinical; Clinical Microbiology; Collaborations; Commit; Congo Red; Coupled; Development; Ear; Endophthalmitis; Eye; Focal Infection; General Hospitals; Generations; Genetic; Goals; In Vitro; Infection; Infection prevention; Institution; Instruction; Investigation; Lactams; Lead; Libraries; Massachusetts; Microbial Biofilms; Modeling; Molecular; Molecular Biology; Molecular Genetics; Multi-Drug Resistance; Mus; Nosocomial Infections; Pathogenesis; Physiology; Public Health; Research Personnel; Resistance; Running; Science; Staphylococcus aureus; Structure; System; Testing; Tissues; Toxic effect; United States National Institutes of Health; Universities; Ursidae Family; Vancomycin Resistance; Vancomycin-resistant S. aureus; Walkers; Work; base; college; combat; design; experience; follow-up; high throughput screening; in vivo; inhibitor/antagonist; innovation; knowledge base; medical schools; methicillin resistant Staphylococcus aureus; mortality; multidisciplinary; novel; novel strategies; pathogen; pre-clinical; programs; tool; transmission process

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

PPG描述（由申请方提供）：MRSA是严重侵入性感染和死亡的主要原因。随着VRE（多重耐药医院感染的主要原因）对万古霉素的耐药性的引入，这一点变得紧迫。PPG的主题是“基于新型化合物筛选和对抗生素耐药性发展、生理学和传播的理解，对抗MRSA和VRE感染的新方法”。PPG的目标是通过向开发管道提供可交付的10种经验证的化合物来改变治疗模式，以治疗这些感染，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，包括创造性的新筛选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深入了解。这种合作伙伴关系，在高通量筛选/跟进化学，生物化学，分子生物学，分子遗传学，分子发病机理和临床微生物学的专业知识，带来了跨越哈佛大学- MGH，HMS，哈佛学院和马萨诸塞州的机构的观点和资产。眼耳医院-承担。所有项目负责人都是各自领域的领导者，组成了一个具有非凡科学广度和成就以及行政经验的团队。协同作用使第一年取得了重大进展。在步行者项目中产生了用于抑制MRSA WTA合成的初始先导物和第二优化结构。与Gilmore小组合作，这些化合物显示在哺乳动物组织中有效，无毒，并且对MSSA和MRSA的临床分离株具有低MIC;此外，WTA缺陷型菌株对刚果红和其他偶氮化合物极其敏感，导致在拟定期间设计新的筛选。与Mylonakis/Ausubel和Hooper小组的合作工作表明，WTA缺陷S。金黄色葡萄球菌可以成功地用β-内酰胺类药物治疗C. elegans和鼠模型。这一系列的研究贯穿了所有的研究小组，第二代WTA抑制剂现在正在通过NIH临床前开发管道推进。 相关性：三个项目采用独立、创新和最先进的方法来确定治疗MRSA、VRE和VRSA感染的先导化合物，并扩大其活动基础的知识基础。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。其中一种化合物已经得到验证，该计划的目标是沿着推进相关科学，再提供10种化合物