POPULATION GENETICS & EVOLUTION OF ANTIBIOTIC RESISTANCE

大肠埃希菌中引起抗生素耐药性的染色体突变 Coli将被用来研究不断增加的 抗药性细菌，并作为增加我们的 对细菌适应性进化过程的理解。这个 这项研究的总体目标是：(一)量化 抗生素耐药性突变如何损害细菌的适合性 这些抗性的代价是通过自然选择和(Ii) 阐明适应的遗传学和生理学基础 抗药性突变的适应成本。为了实现这些目标， 拟议的研究将集中在大肠杆菌的实验种群上， 对链霉素耐药的特征明确的突变 (RpsL)和利福平(RpoB)。这些突变会降低细菌的适合度 分别损害mRNA的翻译和DNA的转录。这些 耐药菌株将在没有抗生素和 监测更高适合度突变体的进化。后者可以 是rpsL或rpoB基因座的敏感回复体，或者，正如我们现在所说的那样 结果表明，携带第二位点代偿突变的菌株 这在保持抵抗力的同时增加了体能。基因， 这些适应的分子和生理基础将被分析。 此外，稳态下的自适应进化的数学模型 细菌种群和受周期性影响的细菌种群 将开发瓶颈，并独立分析它们的属性 这些模型和实验的参数估计 受控条件将允许直接测试预测 这一理论的价值。除了有助于我们理解 种群动态以及遗传和生理基础的研究 在细菌种群中的适应性进化，这些研究直接 对人类健康问题的影响，抗生素的传播 抗药性病原体。这项研究的目的是调查 抗生素耐药性和适应这些成本的性质，是 对于预测抗生素使用率和 抗生素耐药性的流行病学，并用于设计多个 抗生素的使用方案应尽量减少耐药性问题。

Chromosomal mutations conferring antibiotic resistance in Escherichia coli will be used to study the problem of increasing levels of antibiotic-resistant bacteria, and as a tool to increase our understanding of the process of adaptive evolution in bacteria. The overall goals of the study are (i) to quantify the extent to which antibiotic resistance mutations impair the fitness of bacteria, and how these costs of resistance are modified by natural selection and (ii) to elucidate the genetic and physiological bases of adaptations to the fitness costs of resistance mutations. To achieve these goals, the proposed research will focus on experimental populations of E. coli with well-characterized mutations conferring resistance to streptomycin (rpsL) and rifampin (rpoB). These mutations reduce bacterial fitness by impairing mRNA translation and DNA transcription, respectively. These resistant strains will be maintained in the absence of antibiotics and monitored for the evolution of higher fitness mutants. The latter could be sensitive revertants at the rpsL or rpoB loci or, as our present results suggest, strains carrying second site compensatory mutations that increase fitness while maintaining resistance. The genetic, molecular and physiological basis of these adaptations will be analyzed. Additionally, mathematical models of adaptive evolution in steady-state populations of bacteria and bacterial populations subject to periodic bottlenecks will be developed, and their properties analyzed independent estimates of the parameters of these models and experiments under controlled conditions will allow for direct tests of the predictive value of this theory. In addition to contributing to our understanding of the population dynamics and the genetic, and physiological basis of adaptive evolution in bacterial populations, these studies have direct implications for a human health problem, the spread of antibiotic resistant pathogens. The aims of this study, to investigate costs of antibiotic resistance and the nature of adaptation to those costs, are essential for predictions about rates of antibiotic use and the epidemiology of antibiotic resistance, and for the design of multiple antibiotic use protocols that minimize the problems of resistance.