Modeling Pheromone Induced Plasmid and Drug Resistance Transfer

描述（由申请人提供）：粪肠球菌中信息素诱导的共轭pCF10质粒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机制。肠球菌信息素系统的复杂性和独特性存在于两种不同的细胞类型中，与信息素仅作用于同步单一细胞类型的系统相反。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遗传元件位于可通过偶联转移的质粒上。将质粒转移给受体后，受体也接收到质粒上的耐药基因，成为供体。当受体群体达到阈值密度时，偶联发生，信号分子也由供体细胞在染色体上编码时产生，达到临界浓度。随着结合的进行，受体细胞群逐渐变得与供体细胞“相同”。本申请旨在建立随机种群平衡模型，阐明肠球菌质粒pCF10编码的偶联系统的调控机制。为此，我们将首先建立含pcf10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，考虑不同质粒拷贝数的供体和受体细胞并结合随机性的种群平衡模型将被开发，以更好地研究该信号系统在临床相关条件下的行为。实验将进行量化参数和微调模型。这些模型将用于指导抗生素耐药性异化研究的实验设计。通过采用系统方法并考虑种群分布和随机性，该工作将为这一医学上重要的问题引入新的视角，并为共轭抗生素耐药性转移的机制提供更多见解。

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.