Global regulation by mgr in S. aureus

描述（由申请人提供）：金黄色葡萄球菌能够引起广泛的人类疾病。最近，由于细菌对抗生素治疗的耐药性增加，这一问题变得更加严重。因此，迫切需要新的治疗方法。这种生物的致病性可能归因于其产生大量细胞表面相关和细胞外毒力因子的能力。这些毒力决定因素由几个不相关的全球调控位点协调调节。最近，我们已经确定了一个新的基因座mgr，它以一种不同于迄今为止报道的其他系统的模式影响几种毒力因子的产生。我们随后采用遗传和分子方法来绘制和克隆这一全球调控位点。测序，基因特异性突变和互补证实mgr是一个新的位点。我们的数据还表明，mgrA很可能是该基因座中唯一的调控所需基因。在本研究中，我们提出了三个具体的目标：(i)通过研究mgrA基因的转录组织和分析启动子区域来表征mgrA基因座的分子特征；（ii）研究MGR调控靶基因的机制，并利用微阵列技术鉴定其他靶基因；（iii）研究与其他全球调控系统的相互作用和对mgrA基因表达的控制。将采用各种遗传、生化和分子方法来实现这些目标。本建议所述研究的成功完成，将有助我们进一步了解经理规管制度。这一新发现无疑将有助于我们了解金黄色葡萄球菌的全球调控机制，为开发新的治疗方法提供坚实的基础。

DESCRIPTION (provided by applicant): Staphylococcus aureus is capable of causing a wide range of human diseases. It has become more problematic recently due to increasing resistance of the organism to antibiotic treatment. New methods of treatment are therefore urgently needed. The pathogenicity of this organism could be attributed to its ability to produce a large number of cell surface-associated and extracellular virulence factors. These virulence determinants are coordinately regulated by several unlinked global regulatory loci. Recently, we have identified a novel locus, mgr, which affects the production of several virulence factors in a pattern distinct from other systems reported to date. We have subsequently employed genetic and molecular methods to map and clone this global regulatory locus. Sequencing, gene-specific mutation and complementation confirmed that the mgr was a novel locus. Our data also suggest that mgrA is most likely the only gene in this locus that is required in the regulation. In this proposal, we propose to accomplish three specific aims: (i) to molecularly characterize the mgr locus by studying the transcriptional organization and analyzing the promoter region of the mgrA gene; (ii) to investigate the mechanism of target gene regulation by mgr and to identify additional target genes by micorarray technology; (iii) to study interaction with other global regulatory systems and control of mgrA gene expression. Various genetic, biochemical and molecular approaches will be employed to accomplish these aims. The successful completion of the studies outlined in this proposal will provide further insights into the mgr regulatory system. The new knowledge will undoubtedly contribute to our understanding of global regulatory mechanism in S. aureus, which will further provide a solid basis for the development of new treatments.