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 侵袭性耐甲氧西林金黄色葡萄球菌 (MRSA) 感染是导致严重发病的原因 和全球死亡率。 MRSA 感染尤其可怕，因为它们很容易在以下环境中传播： 在医院环境和社区中，他们通常不仅对 β 内酰胺具有耐药性，而且对其他药物也具有耐药性 以及主要类别的抗生素。已经观察到多种化合物的临床耐药性 最近推出用于治疗 MRSA。此外，还有多起有据可查的混合案件。 MRSA 从 VRE 中获得了赋予万古霉素抗性的基因的感染。这个哈佛范围 由 Michael Gilmore 领导的抗生素耐药性项目的成立是为了促进合作 旨在解决 MRSA 抗生素耐药性问题的研究。它汇集了科学家 传染病相关领域的专业知识、感染动物模型、细菌发病机制、细菌 生理学、耐药性的进化、新型抗生素的发现以及新药的探索 克服抗生素耐药性感染的方法。该子项目的重点是发现和 探索对抗 MRSA 的新化合物和策略。三种不同的方法，每种方法都涉及 将研究不同的化合物类别和目标集。目标 1 将评估一个有效且有前途的 新结构类壁磷壁酸抑制剂作为抗 MRSA 药物。目标 II 将解决以下问题的潜力： 作为抗 MRSA 药物的磷壁酸 D-丙氨酰化抑制剂。 Aim III 将提供完整的测试版列表 MRSA 菌株共有的内酰胺增效剂目标，并将探索一种新策略来识别 先前发现的β内酰胺增强剂的目标，以实现进一步的开发。