Modeling Pheromone Induced Plasmid and Drug Resistance Transfer

描述(由申请人提供)： 项目概述粪肠球菌是一种存在于人类肠道和各种生态环境中的细菌。虽然它的毒力不如金黄色葡萄球菌，但它对抗生素的耐药性以及它在人群中传播的容易，长期以来使粪肠球菌成为一个严重的治疗问题。我们拟议的研究将检查粪肠球菌中抗生素耐药性传播的机制。抗生素耐药基因驻留在一个质粒中。同一家族中的不同质粒对不同的抗生素具有耐药性。然而，并不是每个细胞都携带所有的质粒，因为这样做会增加代谢负荷，超过了效率点。因此，每种类型的质粒都必须根据需要在细胞之间传播。抗生素耐药质粒通过称为接合的直接细胞-细胞接触过程传播，在这个过程中，供体细胞将带有抗生素耐药基因的质粒传递给受体细胞。供体细胞携带的质粒会编码用于接合转移的基因以及信号肽。一旦接收到该质粒，受体细胞就会成为供体细胞。长期以来，受者产生的信号肽一直被认为是捐赠者感知受者浓度的“配偶”感应分子。我们目前使用质粒pCF10的研究结果引导我们提出，编码信号的质粒是供体感知自身浓度的“自我”(或法定人数)分子。我们假设，通过这两个信号分子的相互作用，供体细胞和受体细胞改变了它们的结合动力学，以维持它们存在的质粒耐药亚群和无质粒、生长更快的受体亚群。我们进一步假设，一个群体中的供体细胞对“配对”信号的异质反应提供了竞争优势；为了保存资源，一些供体细胞反应较早，信号分子浓度较低，而另一些细胞反应较晚，信号分子浓度较高。细胞反应的滴定是由质粒中的两个操纵子介导的。在我们目前的工作中，我们揭示了一种细胞用来对这两个信号分子做出反应的高贵机制。在这项拟议的研究中，我们将开发数学模型来探索捐赠者和接受者之间的动态关系。更好地理解质粒转移的机制将有助于我们找到对抗接合抗生素耐药转移的新方法。

DESCRIPTION (provided by applicant): Project Summary Enterococcus faecalis is a bacterium found in the intestine of humans as well as in a wide variety of ecological niches. While it is not as virulent as Staphylococcus aureus, it resistance to antibiotics and the ease of its spread among its population has long made E. faecalis a serious therapeutic problem. Our proposed research will examine the mechanism employed for the spread of antibiotic resistance in E. faecalis. The antibiotic resistance gene resides in a plasmid. Different plasmids in the same family carry resistance to different antibiotics. However, each cell does not carry every plasmid, as doing so would increase the metabolic load beyond the point of efficiency. Therefore, each type of plasmid must be spread between cells as necessary. The antibiotic resistant plasmid is spread through a direct cell-cell contact process called conjugation, a process in which the donor cells pass the plasmid with the antibiotic resistance gene to recipient cells. The plasmid carried by donor cells encodes the genes for conjugative transfer of the plasmid as well as for a signal peptide. Upon receipt of the plasmid, the recipient cells then become donor cells. The signal peptide produced by the recipient has long been considered a "mate" sensing molecule for donors to sense the concentration of recipients. Results from our current work using plasmid pCF10 led us to propose that the plasmid encoded signal is a "self" (or quorum) sensing molecule for donor to sense its own concentration. We hypothesize that through the interplay of the two signaling molecules, the donor and recipient cells alter their conjugative dynamics to maintain their plasmid-present antibiotic resistant subpopulation and plasmid- free, faster growing recipient subpopulation. We further hypothesize that a heterogeneous response to the "mate" signal by donor cells in a population provides a competitive advantage; to preserve resources, some donor cells respond earlier and at a low concentration of signaling molecules while others respond later and at a higher concentration of signaling molecules. The titration of the cellular response is mediated by two operons in the plasmid. In our current work we have unveiled a noble mechanism which cells employ to respond to the two signaling molecules. In this proposed research we will develop mathematical models to explore the donor-recipient dynamics. A better understanding of the mechanism of plasmid transfer will help us identify a new way to fight conjugative antibiotic resistance transfer.