Antimicrobials and Efflux Pumps in Staphylococcus aureus Infection

金黄色葡萄球菌感染中的抗菌药物和外排泵

基本信息

批准号：
8202963
负责人：
David C Hooper
金额：
$ 41.29万
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：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8202963
关键词：
Abscess Affect Animal Model Antibiotic Resistance Antibiotics Antimicrobial Resistance Architecture Bacteria Bambermycins Cell Wall Cessation of life Clinical Collaborations Community Hospitals Daptomycin Development Drainage procedure Drug Efflux Environment Exposure to Family Gene Expression Genes Goals Growth HIV Infections Implant In Vitro Infection Injection of therapeutic agent Instruction Laboratories Lactams Linezolid Measurement Membrane Methicillin Resistance Microbial Biofilms Microbial Physiology Modeling Multi-Drug Resistance Mus Nafcillin Operative Surgical Procedures Pathway interactions Pharmaceutical Preparations Plasmids Polymethyl Methacrylate Predisposition Public Health Pump Quinolones Regulation Regulatory Element Regulon Resistance Resistance development Reverse Transcriptase Polymerase Chain Reaction Role Staphylococcus aureus Stress Testing Tetracyclines Transcript Up-Regulation Vancomycin Vancomycin-resistant S. aureus Walkers Work antimicrobial base design effective therapy efflux pump fitness genetic analysis genetic manipulation genome sequencing in vivo interdisciplinary approach local drug delivery methicillin resistant Staphylococcus aureus mortality mouse model mutant new therapeutic target novel novel therapeutics overexpression pathogen prevent programs renal abscess resistance mechanism response subcutaneous transmission process

项目摘要

PROJECT SUMMARY (See Instructions): The longterm goals of the project are to identify the full array of efflux pumps of Staphylococcus aureus that contribute to multiple antimicrobial resistance and to elucidate the determinants of their expression, their role in microbial physiology and their effect on bacterial response to antimicrobials in infection. The work will focus on genetic analysis of regulatory elements and on bacterial fitness and response to antimicrobials in a subcutaneous abscess model, collaborating with other project groups to assess the efficacy of novel antimicrobial compounds in abscesses and the extent to which efflux pumps affect that efficacy. There are four specific aims: 1) assess the effects of NorB, NorD, and Tet38 efflux pumps and their regulators on response to antimicrobials in animal models of infection; 2) evaluate the regulation of expression of abcA encoding an ABC family efflux pump and assess its effects on membrane and cell wall-targeting agents; 3) analyze the global array of pumps over expressed in an abscess environment and determine their contribution to resistance to established agents and novel compounds; and 4) test novel compounds discovered in other subprojects of the program project for resistance to efflux pump expression and for efficacy and development of resistance in mammalian infection models. The work will utilize genetic manipulation and allelic exchange in S. aureus, measurements of gene expression with RT-PCR, and established murine models of infection (subcutaneous abscess, renal abscess, lethality) utilizing a genomically defined strains of methicillin resistant and other S. aureus. The overall goal of the program project is to take a well-integrated, multidisciplinary approach to understanding antibiotic resistance development and transmission, and to integrate that effort with the search for compounds that compromise resistant pathogens, including methicillin-resistant S. aureus (MRSA), by inhibiting novel targets and pathways. This project will add to understanding of resistance mechanisms related to multidrug efflux pumps and provide strains for testing the effect of such pumps on novel compounds active against new targets and pathways. It will also utilize mammalian models of a common MRSA infection to test compound activity in vivo.

项目摘要（参见说明）：该项目的长期目标是确定金黄色葡萄球菌的全套外排泵，这些外排泵有助于多种抗菌药物耐药性，并阐明其表达的决定因素、它们在微生物生理学中的作用以及它们对感染中细菌对抗菌药物反应的影响。这项工作将重点关注皮下脓肿模型中调节元件的遗传分析以及细菌适应性和对抗菌药物的反应，与其他项目组合作评估新型抗菌化合物在脓肿中的功效以及外排泵影响该功效的程度。有四个具体目标：1）评估 NorB、NorD 和 Tet38 外排泵及其调节器对感染动物模型中抗菌药物反应的影响； 2)评估编码ABC家族外排泵的abcA的表达调节并评估其对膜和细胞壁靶向剂的影响； 3) 分析脓肿环境中过度表达的泵的整体阵列，并确定它们对既定药物和新型化合物的耐药性的贡献； 4) 测试在该计划项目的其他子项目中发现的新化合物对外排泵表达的抗性以及在哺乳动物感染模型中的功效和抗性的发展。这项工作将利用金黄色葡萄球菌的基因操作和等位基因交换，通过 RT-PCR 测量基因表达，并利用基因组确定的甲氧西林耐药菌株和其他金黄色葡萄球菌菌株建立感染的小鼠模型（皮下脓肿、肾脓肿、致死率）。金黄色葡萄球菌。该计划项目的总体目标是采取一种综合的、多学科的方法来了解抗生素耐药性的发展和传播，并将这一努力与寻找损害耐药病原体的化合物相结合，包括耐甲氧西林金黄色葡萄球菌（MRSA），通过抑制新的靶标和途径。该项目将加深对与多药外排泵相关的耐药机制的理解，并提供用于测试此类泵对针对新靶点和途径的新型化合物的影响的菌株。它还将利用常见 MRSA 感染的哺乳动物模型来测试化合物的体内活性。