Harvard-wide Program on Antibiotic Resistance

哈佛大学抗生素耐药性计划

基本信息

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
项目类别：
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

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

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项目摘要

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的描述（申请人提供）：MRSA是严重侵入性感染和死亡率的主要原因。 VRE引入万古霉素耐药性（多药耐药医院感染的主要原因）变得紧急。 PPG主题是“基于新颖的化合物筛选以及对抗生素耐药性的发育，生理学和传播的理解，用于对抗MRSA和VRE感染的新方法”。 PPG旨在通过将开发管道作为可交付成果提供，10种验证的化合物来治疗这些感染〜，同时对基础科学取得了重大进步，从而改变了治疗范例。跨学科团队将采用一种创新的学术方法，涉及创新的新屏幕和基于信息的化合物识别，并对抗生素耐药性及其传播的分子生物学有了深入的了解。这种合作伙伴关系具有高吞吐量筛查/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的观点和资产，这些机构 - 哈佛大学 - MGH，HMS，HMS，HASSCARD COLLECT，HAFFARD COLLECT和MASS。EYE.ERE.EIRE和EAR HERIMERIRM。所有项目领导者都是各自领域的领导者，包括一支由不寻常的科学广度和成就和行政经验的团队。 Synergy允许在第一年取得重大进步。 Walker项目中生成了初始铅和第二个用于抑制MRSA WTA合成的结构。这些化合物与吉尔莫尔组合作，在哺乳动物组织中有效，无毒，并且对于MSSA和MRSA的临床分离株的麦克风含量低。此外，WTA缺乏菌株对刚果红色和其他偶氮化合物极为敏感，从而导致在拟议时期设计新屏幕。与Mylonakis/Ausubel和Hooper群体的合作工作表明，WTA有缺陷的金黄色葡萄球菌可以在C. exkemans和Murine模型中分别成功用B-莱克姆治疗。这条调查贯穿了所有组，第二代WTA抑制剂现在正在通过NIH临床前开发管道前进。相关性：三个项目采用了识别用于治疗MRSA，VRE和VRSA感染的铅化合物的独立，创新和最先进的方法，并扩大了其活动构成的知识库。其他两个项目在体外和体内测试了这些化合物，并确定它们与抗生素耐药性和耐药性传播的关系。一个化合物已经得到了验证，该计划的目的是再提供10个，并推进随之而来的科学