Subproject 1 Compounds and Strategies for Treating MRSA and VRE

子项目 1 治疗 MRSA 和 VRE 的化合物和策略

• 批准号: 9151286
• 负责人: Suzanne Walker
• 金额: $ 54.84万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151286
• 关键词: Acute; Address; Alanine; Aminoglycoside Antibiotics; Aminoglycoside resistance; Anabolism; Animal Model; Antibiotic Resistance; Antibiotics; Antimicrobial Cationic Peptides; Area; Attention; Autolysin; Bacterial Infections; Bacterial Physiology; Candidate Disease Gene; Cell surface; Cells; Cessation of life; Clinical; Collaborations; Communicable Diseases; Communities; Development; Drug Kinetics; Enzymes; Evaluation; Evolution; Fostering; Genes; Genetic; Hospitals; Immune system; Individual; Infection; Inflammation; Integration Host Factors; Libraries; Longevity; Mediating; Microbial Biofilms; Morbidity - disease rate; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptidoglycan; Peptidyltransferase; Phenotype; Phospholipase A2; Play; Polymers; Regulation; Research; Resistance; Risk; Role; Scientist; Serum; Staphylococcus aureus; Structure; Structure-Activity Relationship; Teichoic Acids; Testing; United States; Validation; Vancomycin; Vancomycin Resistance; Virulent; Work; analog; bacterial resistance; base; beta-Lactam Resistance; beta-Lactams; combat; crosslink; density; follow-up; genome sequencing; high throughput screening; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; mortality; mouse model; mutant; novel; novel strategies; prevent; programs; screening; whole genome

ABSTRACT Invasive methicillin resistant Staphylococcus aureus (MRSA) infections are responsible for significant morbidity and mortality worldwide. MRSA infections are particularly frightening since they are readily transmitted both in hospital settings and in the community, and they are typically resistant not only to beta lactams, but to other major classes of antibiotics as well. Clinical resistance has already been observed to several compounds introduced recently to treat MRSA. Moreover, there have been several well-documented cases involving mixed infections in which MRSA acquired genes conferring vancomycin resistance from VRE. This Harvard-wide Program Project on antibiotic resistance, led by Michael Gilmore, was established to foster collaborative research aimed at addressing the problem of antibiotic resistance in MRSA. It brings together scientists with expertise in relevant areas of infectious disease, animal models of infection, bacterial pathogenesis, bacterial physiology, the evolution of resistance, the discovery of novel antibiotics, and the exploration of new approaches to overcome antibiotic resistant infections. This subproject is focused on the discovery and exploration of novel compounds and strategies to combat MRSA. Three different approaches, each involving different compound classes and sets of targets, will be investigated. Aim 1 will evaluate a potent and promising new structural class of wall teichoic acid inhibitors as anti-MRSA agents. Aim II will address the potential of inhibitors of teichoic acid D-alanylation as anti-MRSA agents. Aim III will provide a comprehensive list of beta lactam potentiator targets that are shared among MRSA strains, and will explore a new strategy to identify targets of previously discovered beta lactam potentiators to enable further development.

抽象的 侵入性甲氧西林金黄色葡萄球菌（MRSA）感染负责显着发病 和全球死亡率。 MRSA感染特别令人恐惧，因为它们很容易传输到 医院环境和社区中，它们通常不仅对βlactams具有抵抗力，而且对其他 抗生素的主要类别。已经观察到几种化合物的临床阻力 最近引入了治疗MRSA。此外，已经有几个有据可查的案例涉及混合 MRSA获得从VRE赋予万古霉素耐药性的基因的感染。这是哈佛大学的 由迈克尔·吉尔莫尔（Michael Gilmore）领导的抗生素抗性计划项目的成立是为了促进合作 旨在解决MRSA抗生素抗性问题的研究。它汇集了科学家 相关领域的专业知识，感染动物模型，细菌发病机理，细菌 生理学，抗性的进化，新型抗生素的发现以及新的探索 克服抗生素耐药感染的方法。该子标记的重点是发现和 探索新颖的化合物和与MRSA作斗争的策略。三种不同的方法，每种方法涉及 将研究不同的化合物类别和一组目标。 AIM 1将评估有力而有前途的 新的结构类别的壁teicic酸抑制剂作为抗MRSA剂。 AIM II将解决潜力 Teichoic Acid D-丙二醇作为抗MRSA剂的抑制剂。 AIM III将提供Beta的全面清单 LACTAM增强剂目标在MRSA菌株之间共享，并将探索一种新策略以识别 先前发现的β乳丹乳杆菌稳定器的靶标可以进一步发展。