Harvard-wide Program on Antibiotic Resistance

哈佛大学抗生素耐药性计划

• 批准号: 8716642
• 负责人: Frederick M Ausubel
• 金额: $ 215.82万
• 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/8716642
• 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（由申请人提供）：MRSA 是严重侵袭性感染和死亡的主要原因。随着 VRE（多重耐药性医院感染的主要原因）引入万古霉素耐药性，这一问题变得紧迫。 PPG 的主题是“基于新型化合物筛选以及对抗生素耐药性的发展、生理学和传播的了解，对抗 MRSA 和 VRE 感染的新方法”。 PPG 旨在通过向开发管道提供 10 种经过验证的化合物作为可交付成果来改变治疗模式，同时在基础科学方面取得重大进展。该跨学科团队将采用创新的学术方法，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/后续化学、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拥有专业知识，带来了哈佛大学各机构的观点和资产——MGH、HMS、哈佛大学和麻省大学眼耳医务室——承受。所有项目负责人都是各自领域的领导者，由一支具有不同寻常的科学广度和成就以及管理经验的团队组成。协同作用在第一年就取得了重大进展。 Walker 项目产生了最初的先导化合物和第二个用于抑制 MRSA WTA 合成的优化结构。与 Gilmore 小组合作，这些化合物被证明对哺乳动物组织有效、无毒，并且对临床分离的 MSSA 和 MRSA 具有较低的 MIC；此外，WTA 缺陷菌株对刚果红和其他偶氮化合物极其敏感，因此需要为拟议时期设计新的筛选。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秀丽隐杆线虫和小鼠模型中成功地用 β-内酰胺治疗。这一研究贯穿了所有小组，第二代 WTA 抑制剂目前正在 NIH 临床前开发管道中推进。 相关性：三个项目采用独立、创新和最先进的方法来识别治疗 MRSA、VRE 和 VRSA 感染的先导化合物，并扩展其活动的知识基础。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。一种化合物已经得到验证，该计划的目标是提供另外 10 种化合物，同时推进相关科学的发展