Modeling Pheromone Induced Plasmid and Drug Resistance Transfer

描述（由申请人提供）： 粪肠球菌（Enterococcus faecalis）是一种存在于人类肠道以及各种生态环境中的细菌。虽然它的毒性不如金黄色葡萄球菌，但它对抗生素的耐药性以及在人群中传播的容易性长期以来一直使E。粪便是严重的治疗问题。我们拟议的研究将检查大肠杆菌抗生素耐药性传播的机制。粪便抗生素抗性基因存在于质粒中。同一家族中的不同质粒携带对不同抗生素的耐药性。然而，每个细胞并不携带每个质粒，因为这样做会增加代谢负荷超过效率点。因此，每种类型的质粒必须根据需要在细胞之间扩散。抗生素抗性质粒通过称为接合的直接细胞-细胞接触过程传播，该过程中供体细胞将具有抗生素抗性基因的质粒传递给受体细胞。供体细胞携带的质粒编码用于质粒接合转移以及信号肽的基因。在接受质粒后，受体细胞然后变成供体细胞。受体产生的信号肽一直被认为是供者感知受体浓度的“配偶”感应分子。我们目前使用质粒pCF 10的工作结果使我们提出质粒编码的信号是供体感知其自身浓度的“自我”（或群体）传感分子。我们假设，通过两种信号分子的相互作用，供体和受体细胞改变其接合动力学，以维持其质粒存在的抗生素耐药亚群和无质粒、生长更快的受体亚群。我们进一步假设群体中供体细胞对“交配”信号的异质反应提供了竞争优势;为了保护资源，一些供体细胞反应较早且信号分子浓度较低，而另一些细胞反应较晚且信号分子浓度较高。细胞反应的滴定由质粒中的两个操纵子介导。在我们目前的工作中，我们已经揭示了细胞对这两种信号分子做出反应的一种重要机制。在这项拟议的研究中，我们将开发数学模型来探索捐助者-受援国的动态。对质粒转移机制的深入了解将有助于我们找到一种新的方法来对抗接合抗生素耐药性的转移。

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.