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

项目摘要/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- 中介综合征，有些危及生命，影响所有年龄段的患者。作为一个物种，金黄色葡萄球菌 对临床上设计使用的所有类别的抗生素产生抗药性。疾病 由对甲氧西林耐药的菌株引起的所谓的MRSA菌株在去年在美国流行 十年。这些分离株的高流行率需要新的抗菌药来治疗MRSA 对包括青霉素和头孢菌素在内的所有可用SS-内酰胺类抗生素耐药的菌株。 此外，糖肽抗生素万古霉素的有效性，长期以来被认为是最后的抗生素 由于全球金黄色葡萄球菌和金黄色葡萄球菌之间敏感性的下降，对MRSA感染的求助已经开始减少 HVISA、VISA和VRSA分离株的研制我们的重点是两个分量的信号 感受细胞壁压力的转导操纵子，并被多种细胞壁活性抗菌剂激活。 一旦被激活，这个系统就会影响各种基因的转录，上调一些基因，然后下调- 规范他人。这种操纵子被称为VraSR的失活，甚至产生了对甲氧西林敏感的表型 在带有mecA的菌株中，该基因与MRSA表型有关。抗药性产生的机制 这些突变体中的表型是否被烧毁尚不清楚。我们计划评估进一步受制于 这种细胞壁压力操纵子的基因操作，以了解其在影响耐甲氧西林金黄色葡萄球菌耐药性中的作用 表型。这些研究应该为MRSA分离株逃避的机制提供进一步的洞察。 抗菌治疗，为寻找新的抗菌治疗靶点奠定基础。

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.