POPULATION GENETICS & EVOLUTION OF ANTIBIOTIC RESISTANCE

群体遗传学

• 批准号: 2887353
• 负责人: Bruce Richard Levin
• 金额: $ 13.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887353
• 关键词: Escherichia coli; alleles; antibiotics; bacterial genetics; biochemical evolution; chromosome aberrations; drug resistance; environmental adaptation; gene expression; genetic transcription; genetic translation; mathematical model; microorganism population study; model design /development; natural selections; nucleic acid sequence; protein biosynthesis; rifamycins; statistics /biometry; streptomycin

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.

染色体突变赋予埃希氏菌抗生素耐药性 大肠杆菌将被用来研究增加水平的问题 抗生素耐药性细菌，并作为增加我们的工具 了解细菌的适应性进化过程。这 该研究的总体目标是 (i) 量化 抗生素耐药性突变会损害细菌的健康，以及如何 这些抵抗成本通过自然选择而改变，并且（ii） 阐明适应的遗传和生理基础 抗性突变的适应成本。为了实现这些目标， 拟议的研究将集中于大肠杆菌的实验种群 明确表征的突变赋予链霉素抗性 (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 在没有抗生素的情况下，耐药菌株将得以维持 监测更高适应性突变体的进化。后者可以 是 rpsL 或 rpoB 位点的敏感回复突变体，或者如我们目前的 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强健康。遗传的， 将分析这些适应的分子和生理学基础。 此外，稳态适应性进化的数学模型 细菌种群和细菌种群受到定期 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预测 这一理论的价值。除了有助于我们的理解 种群动态以及遗传和生理基础 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问题的影响 耐药病原体。本研究的目的是调查成本 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，以及多重设计 最大限度地减少耐药性问题的抗生素使用方案。