Role of Signal Transduction in Resistance to Cell-Wall Antimicrobials in MRSA

信号转导在 MRSA 细胞壁抗菌药物耐药性中的作用

• 批准号: 8090590
• 负责人: SUSAN BOYLE-VAVRA
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-02 至 2011-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090590
• 关键词: Address; Affect; Age; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Cell Wall; Cephalosporins; Chemical Structure; Clinical; Communities; Development; Disease; Effectiveness; Environment; Epidemic; Evaluation; Genes; Genetic Transcription; Glycopeptide Antibiotics; Glycopeptides; Goals; Growth; Healthcare; High Prevalence; Homologous Gene; In Vitro; Infection; Intermediate resistance; Lead; Life; Lung; Mediating; Methicillin; Methodology; Modeling; Monobactams; Mus; Open Reading Frames; Operon; Oxacillin; Patients; Penicillins; Peptidoglycan; Phase; Phenotype; Proteins; Public Health; Regulator Genes; Regulon; Reporting; Research; Resistance; Resistance development; Resort; Role; Signal Induction; Signal Transduction; Staphylococcus aureus; Stress; Syndrome; System; Testing; Toxin; Vancomycin; Vancomycin-resistant S. aureus; abstracting; antimicrobial; base; biological adaptation to stress; combat; design; gene synthesis; genetic manipulation; in vivo; insight; interest; killings; methicillin resistant Staphylococcus aureus; mouse model; mutant; novel; novel therapeutics; progesterone 11-hemisuccinate-(2-iodohistamine); research study; resistance mechanism

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus is the leading cause of community and nosocomially-acquired infectious and toxin- mediated syndromes, some life-threatening that affect patients of all ages. As a species, S. aureus has become resistant to antibiotics of all classes that have been designed for use in the clinical arena. Disease caused by isolates resistant to methicillin, so-called MRSA isolates, has become epidemic in the US in the last decade. The high prevalence of these isolates necessitates a need for new antimicrobials to treat MRSA isolates that are resistant to all available ss-lactam antibiotics including penicillins and cephalosporins. Moreover, the effectiveness of the glycopeptide antibiotic vancomycin, long regarded as the antibiotic of last resort for MRSA infections, has begun to decrease due to globally decreasing sensitivity among S. aureus and the development of hVISA, VISA and VRSA isolates. Our focus has been on a two-component signal transduction operon that senses cell wall stress and is activated by a variety of cell wall-active antimicrobials. Once activated, this system affects the transcription of a variety of genes, upregulating some and down- regulating others. Inactivation of this operon, called VraSR, produces a methicillin-susceptible phenotype even in strains that have mecA, the gene conferring the MRSA phenotype. The mechanism by which the resistant phenotype is ablated in these mutants is not clear. We plan to evaluate the consequences of further subjecting this cell wall stress operon to genetic manipulation to understand its role in effecting the MRSA resistance phenotype. These studies should provide further insight into the mechanisms by which MRSA isolates elude antimicrobial therapy and form the basis for the search for new targets for antimicrobial therapy.

项目总结/摘要 金黄色葡萄球菌是社区和医院获得性感染和毒素的主要原因， 介导的综合征，有些危及生命，影响所有年龄段的患者。作为一个种，S.金黄色葡萄球菌 对设计用于临床竞技场的所有类别的抗生素产生耐药性。疾病 由对甲氧西林耐药的分离株，即所谓的MRSA分离株引起的， 十年这些分离株的高流行率需要新的抗菌药物来治疗MRSA 对所有可用的β-内酰胺抗生素包括青霉素和头孢菌素具有抗性的分离株。 此外，长期以来被认为是最后一种抗生素的糖肽类抗生素万古霉素的有效性 由于全球范围内S.金黄色葡萄球菌和 hVISA、VISA和VRSA分离株的开发。我们的重点是一个双分量信号 转导操纵子，其感知细胞壁应激并被多种细胞壁活性抗微生物剂激活。 一旦被激活，这个系统会影响多种基因的转录，上调一些基因，下调一些基因。 规范其他人。这种操纵子（称为VraSR）的失活产生了甲氧西林敏感表型， 在具有mecA的菌株中，该基因赋予MRSA表型。抗药性的机制 表型在这些突变体中是否消失尚不清楚。我们计划评估进一步加强 这种细胞壁应力操纵子的遗传操作，以了解其在影响耐甲氧西林金黄色葡萄球菌的作用 表型这些研究将为MRSA分离株逃避耐药的机制提供进一步的见解。 这些新的靶点为抗微生物治疗提供了新的靶点，并形成了寻找抗微生物治疗新靶点的基础。