POPULATION GENETICS & EVOLUTION OF ANTIBIOTIC RESISTANCE

大肠埃希氏菌耐药性的染色体突变 大肠杆菌将被用来研究增加水平的问题， 作为一种工具， 了解细菌的适应性进化过程。的 研究的总体目标是：（一）量化 抗生素耐药性突变损害了细菌的适应性，以及如何 这些抗性的代价通过自然选择而改变，以及（ii） 阐明适应的遗传和生理基础， 抗性突变的适应性成本。为了实现这些目标， 拟议的研究将集中在E.杆菌 对链霉素产生耐药性的特征明确的突变 （rpsL）和利福平（rpoB）。这些突变降低了细菌的适应性， 分别损害mRNA翻译和DNA转录。这些 耐药菌株将在不存在抗生素的情况下维持， 监测更高适应性突变体的进化。后者可以 在rpsL或rpoB基因座上是敏感的回复突变体，或者，正如我们目前所发现的， 结果表明，携带第二位点补偿突变的菌株 在保持抵抗力的同时增加健康。基因， 这些适应的分子和生理基础将被分析。 此外，稳态自适应进化的数学模型 细菌种群和细菌种群受到周期性的 将开发瓶颈，并独立分析其属性 这些模型和实验的参数估计， 受控条件将允许直接测试的预测 这个理论的价值。除了有助于我们理解 的种群动态和遗传，生理基础， 细菌种群的适应性进化，这些研究直接 抗生素的传播对人类健康的影响 耐药病原体。本研究的目的是调查 抗生素耐药性和适应这些成本的性质， 对于预测抗生素使用率和 抗生素耐药性的流行病学，并为设计多个 抗生素使用协议，尽量减少耐药性的问题。

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.