Modeling Pheromone Induced Plasmid and Drug Resistance Transfer

描述(由申请人提供)：信息素诱导的接合pCF10质粒在粪肠球菌中的转移与抗生素耐药性的传播有关，有助于机会性肠球菌感染的发病。肠球菌信息素系统的复杂性和独特性存在于所涉及的两种不同的细胞类型中，而不是信息素仅作用于同步单一细胞类型的种群的系统。宿主细胞染色体编码信号分子，而负责感知和响应信号分子的基因元件位于可通过接合传递的质粒上。一旦将质粒转移到受体，受体也会收到该质粒上的耐药基因，并成为供体。当受体群体达到阈值密度，信号分子也是供体细胞在染色体上编码时产生的信号分子达到临界浓度时，就会发生接合。随着接合过程的进行，受体细胞群逐渐变得与供体细胞“相同”。本申请旨在建立一个随机种群平衡模型，以阐明肠球菌质粒pCF10编码的接合系统的调控机制。为此，我们将首先建立含有pCF10的细胞(供体细胞)的确定性数学模型，以评估cCF10信息素系统的动力学和稳定性行为。随后，将建立一个种群平衡模型，该模型考虑了不同拷贝数的供体和受体细胞，并结合了随机性，以更好地检验该信号系统在临床相关条件下的行为。将进行实验以量化参数并对模型进行微调。这些模型将用于指导研究抗生素耐药性异化的实验设计。这项工作，通过采取系统的方法并考虑种群分布和随机性，将为这一医学上重要的问题引入一个新的视角，并为结合抗生素耐药性转移的机制提供更多的见解。

DESCRIPTION (provided by applicant): Pheromone-induced conjugative pCF10 plasmid transfer in Enterococcus faecalis is implicated in the transmission of antibiotic resistance contributing to the pathogenesis of opportunistic enterococcal infections. The complexity and the unique features of the Enterococcus pheromone system reside in the two distinct cell types involved, in contrast to systems in which pheromone merely acts to synchronize a population of a single cell type. The host cell chromosome encodes the signaling molecule while the genetic elements responsible for sensing and responding to the signaling molecule are on a plasmid that is transferable by conjugation. Upon the transfer of the plasmid to the recipient, the recipient also receives the drug resistance gene on the plasmid and becomes a donor. Conjugation occurs when the recipient population reaches a threshold density and the signaling molecule, which is also produced by the donor cell as it is encoded on the chromosome, reaches a critical concentration. As conjugation proceeds, the recipient cell population gradually becomes "identical" to the donor cell. This application aims to develop a stochastic population balance model to elucidate the regulatory mechanism of the conjugation system encoded by the enterococcal plasmid pCF10. To that end we will first develop a deterministic mathematical model for pCF10-containing cell (donor cell) to assess the dynamics and the stability behavior of the cCF10 pheromone system. Subsequently a population balance model which considers donors of different plasmid copy numbers and recipient cells and incorporates stochasticity will be developed to better examine the behavior of this signaling system under clinically relevant conditions. Experimentation will be carried out to quantify the parameters and fine tune the model. The models will be used to guide experimental design for investigation of the dissimilation of antibiotic resistance. The work, by taking a systems approach and considering population distribution and stochasticity, will introduce a fresh perspective on this medically important problem and provide much insight into the mechanism of conjugational antibiotic resistance transfer.