Modeling Pheromone Induced Plasmid and Drug Resistance Transfer

信息素诱导质粒和耐药性转移建模

• 批准号: 7298035
• 负责人: WEI-SHOU HU
• 金额: $ 20.44万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-16 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7298035
• 关键词: Antibiotic Resistance; Behavior; Binding; Cell Communication; Cells; Chromosomes; Condition; Drug resistance; Elements; Enterococcus; Enterococcus faecalis; Equilibrium; Experimental Designs; Genes; Genetic; Gram-Positive Bacteria; Infection; Investigation; Modeling; Molecular; Molecular Structure; Nature; Numbers; Operon; Pathogenesis; Peptides; Pheromone; Plasmids; Population; Population Distributions; Proteins; Regulation; Research; Signal Transduction; Signaling Molecule; Surface; System; Systems Analysis; Transcript; Work; cell type; clinically relevant; density; genetic element; genetic regulatory protein; insight; mathematical model; microorganism; peptide pheromone cCF10; prevent; quorum sensing; transmission process

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.

描述（由申请人提供）：粪肠球菌中信息素诱导的接合性pCF10质粒转移涉及抗生素耐药性的传播，从而导致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特征在于所涉及的两种不同的细胞类型，这与信息素仅用于同步单一细胞类型群体的系统相反。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接合转移的质粒上。当质粒转移给接受者时，接受者也接受了质粒上的耐药基因并成为供体。当受体群体达到阈值密度并且信号分子（也由供体细胞在染色体上编码时产生）达到临界浓度时，就会发生接合。随着接合的进行，受体细胞群逐渐变得与供体细胞“相同”。本申请旨在开发随机群体平衡模型，以阐明肠球菌质粒 pCF10 编码的接合系统的调节机制。为此，我们将首先为包含 pCF10 的细胞（供体细胞）开发确定性数学模型，以评估 cCF10 信息素系统的动力学和稳定性行为。随后，将开发考虑不同质粒拷贝数的供体和受体细胞并纳入随机性的群体平衡模型，以更好地检查该信号系统在临床相关条件下的行为。将进行实验来量化参数并微调模型。该模型将用于指导研究抗生素耐药性异化的实验设计。这项工作通过采用系统方法并考虑群体分布和随机性，将为这一重要的医学问题引入新的视角，并为结合抗生素耐药性转移的机制提供更多见解。