Genetic Functions of an Enterococcal R Factor

描述（由申请方提供）：粪肠球菌是医院获得性感染的主要原因，在将抗生素耐药性和毒力基因传播给其他细菌病原体方面也起着关键作用。该申请寻求对独特的基于肽的信号传导系统的基础研究的持续支持，该信号传导系统允许携带称为pCF 10的抗生素抗性/毒力质粒的细胞调节参与抗性转移和毒力的基因的表达。信号系统中的关键参与者包括cCF 10肽信息素（信号分子）和拮抗cCF 10的iCF 10肽信息素抑制剂。这些肽的受体是称为PrgX的转录因子，其调节编码毒力和质粒转移基因的pCF 10 prgQ操纵子的表达。信息素反应机制包括一个敏感而强大的生物开关，其中多个调节电路协同作用以放大对信息素的直接反应，并使宿主细胞能够感知不同种类的环境线索。涉及新的小RNA的转录后调节机制也在信息素反应中发挥重要作用。拟议的研究集中在阐明各种监管电路的定量效应机制方面，并确定的机制，信息素诱导的状态可以返回到基础水平的表达质粒转移到一个新的主机。这项工作将揭示通过细胞-细胞信号调节微生物毒力的见解，适用于许多生物体，也可能促进开发抗菌剂的新策略。 公共卫生相关性：这项研究调查了细菌使用小分子信号相互交流的过程。在这种情况下，信号导致携带抗生素抗性基因的细胞将这些基因的拷贝转移到其他细胞中。涉及的细菌种类是粪肠球菌，转移过程增加了引起医院感染的菌株的毒力和抗生素耐药性。从这项研究中获得的基本知识可能为开发更有效的抗菌化疗形式提供新的见解。

DESCRIPTION (provided by applicant): Enterococcus faecalis is a major cause of hospital-acquired infections and also plays a key role in the dissemination of antibiotic resistance and virulence genes to other bacterial pathogens. This application seeks continued support for basic studies of a unique peptide-based signaling system that allows cells carrying an antibiotic resistance/virulence plasmid called pCF10 to regulate expression of genes involved in resistance transfer and virulence. The key players in the signaling system include the cCF10 peptide pheromone (signal molecule) and the iCF10 peptide pheromone inhibitor which antagonizes cCF10. The receptor for these peptides is a transcription factor called PrgX, which regulates expression of the pCF10 prgQ operon encoding the virulence and plasmid transfer genes. The pheromone response machinery comprises a sensitive and robust biological switch, where multiple regulatory circuits act in concert to amplify the direct response to pheromone, and to enable the host cell to sense different kinds of environmental cues. Post-transcriptional regulatory mechanisms involving novel small RNAs also play a major role in the pheromone response. The proposed studies are focused on elucidating the quantitative effects mechanistic aspects of various regulatory circuits, and on determining the mechanisms by which the pheromone-induced state can be returned to basal levels of expression following transfer of the plasmid to a new host. This work will reveal insights into regulation of microbial virulence by cell-cell signaling, applicable to many organisms, and may also facilitate new strategies for development of antimicrobial agents. PUBLIC HEALTH RELEVANCE: This research investigates the process by which bacteria communicate with one another using small molecule signals. In this case the signal causes cells carrying antibiotic resistance genes to transfer copies of these genes to other cells. The bacterial species involved is Enterococcus faecalis and the transfer process increases the virulence and antibiotic resistance of strains that cause infections in hospitals. The basic knowledge gained from this research may provide new insights into the development of more effective forms of antimicrobial chemotherapy.