Population Genetics & Evolution of Antibiotic Resistance

描述（由申请人提供）：获得性抗生素耐药性是指在接受抗生素治疗或预防的宿主体内定植和感染的易感共生细菌和致病菌群体中进化而来的。获得性抗生素耐药性可导致治疗失败，并导致传染性或原发性抗生素耐药性。本申请中提出的研究将致力于以定量和预测的方式了解遗传、细菌、宿主因素和群体动态过程，这些过程负责感染使用单一和多种抗生素的未感染哺乳动物的细菌群体的获得性耐药进化。为此，我们将开发和分析宿主内抗生素治疗群体动态和耐药性进化的数学和计算机模拟模型的特性，并使用荚膜大肠杆菌（018:K1:H7）进行体外和体内（实验室小鼠）实验。在这些实验中，我们将估计这些模型的参数，评估其构建背后假设的真实性，并通过分析其特性来测试预测的有效性。本次调查的目标是；(1)阐明在哪些条件（剂量水平和治疗方案）下，选择有利于感染抗生素敏感菌的未感染哺乳动物的耐药性进化，并使用单一抗生素、多种抗生素和临床耐药需要多重突变的抗生素进行治疗。(2)评估抗生素后效应（暴露于抗生素的细菌在抗生素不再达到抑制浓度后恢复正常生长的延迟）对感染抗生素治疗的哺乳动物的细菌群体获得性耐药进化的贡献。(3)确定突变率升高对进化获得性抗生素耐药性的贡献，以及抗生素介导的选择将导致增加突变率的基因进化的条件，即突变基因。针对这些目标提出的研究在一定程度上是由对细菌适应性进化机制的学术兴趣所激发的。这项研究的动机还在于其对健康科学的直接效用，特别是促进临床有效抗生素治疗方案的设计和评估，以最大限度地减少目标细菌群体中获得性抗生素耐药性演变的可能性。

DESCRIPTION (provided by applicant): Acquired antibiotic resistance is that which evolves in populations of susceptible commensal and pathogenic bacteria colonizing and infecting hosts that are under antibiotic treatment or prophylaxis. Acquired antibiotic resistance can result in treatment failure and contribute to transmissible or primary antibiotic resistance. The research proposed in this application will be devoted to understanding, in a quantitative and predictive way, the genetic, bacterial, host factors and population dynamic processes responsible for the evolution of acquired resistance in populations of bacteria infecting uncompromised mammals treated with single and multiple antibiotics. Towards this end, we will develop and analyze the properties of mathematical and computer simulation models of the within-host population dynamics of antibiotic treatment and the evolution of resistance and perform in vitro and in vivo (laboratory mouse) experiments with a capsulated E. coli (018:K1 :H7). In these experiments, we will estimate the parameters of these models, evaluate the reality of the assumptions behind their construction and test the validity of the predictions made from the analysis of their properties. The goals of this investigation are to; (1) Elucidate the conditions (dosage levels and treatment regimes) under which selection will favor the evolution of resistance in uncompromised mammals infected with antibiotic susceptible bacteria and treated with single antibiotics, multiple antibiotics and antibiotics for which clinical resistance requires multiple mutations. (2) Evaluate the contribution of post antibiotic effects (delays in the resumption of normal growth of antibiotic exposed bacteria after antibiotics are no longer at inhibitory concentrations) to the evolution of acquired resistance in populations of bacteria infecting antibiotic treated mammals. (3) Determine the contribution of elevated mutation rates to evolution acquired antibiotic resistance and the conditions under which antibiotic-mediated selection will result in the evolution of genes that augment mutation rates, mutator genes. The proposed research directed at these goals is in part, motivated by an academic interest in the mechanisms of adaptive evolution in bacteria. This research is also motivated by its direct utility to the health sciences and, in particular, to facilitate the design and evaluation of clinically effective antibiotic treatment protocols that minimize the likelihood of acquired antibiotic resistance evolving in the target population of bacteria.