Genetic Functions of an Enterococcal R Factor

描述（由申请人提供）：粪肠球菌是医院获得性感染的主要原因，在向其他细菌病原体传播抗生素耐药性和毒力基因方面也起着关键作用。本申请旨在继续支持一种独特的基于肽的信号系统的基础研究，该系统允许携带抗生素耐药性/毒力质粒pCF10的细胞调节参与耐药性转移和毒力的基因表达。信号系统的关键参与者包括cCF10肽信息素（信号分子）和拮抗cCF10的iCF10肽信息素抑制剂。这些肽的受体是一种叫做PrgX的转录因子，它调节编码毒力和质粒转移基因的pCF10 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。涉及新型小rna的转录后调控机制也在信息素反应中发挥重要作用。这些研究的重点是阐明各种调控回路的定量效应机制，并确定在质粒转移到新宿主后信息素诱导状态可以恢复到基础表达水平的机制。这项工作将揭示细胞-细胞信号传导对微生物毒力的调控，适用于许多生物体，也可能促进抗菌剂开发的新策略。

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.