Evolution of Antibiotic Resistance in Enteric Bacteria

描述（由申请人提供）：细菌抗生素耐药性的发展和传播已成为一个主要的公共卫生问题。曾经很容易被抗菌药物控制的病原菌现在经常对大多数抗生素无效。大多数关于抗生素耐药性的原因和后果的研究都集中在致病菌的临床分离株上，即从医院感染的人身上分离的菌株。这些研究揭示了耐药机制和基因的多样性，以及耐药如何在细菌谱系之间传播的遗传细节，并提供了对医院环境中这种传播速度的估计。这些临床研究在跟踪抗生素耐药性演变过程和建议针对特定病原体的药物使用优先权方面发挥着至关重要的作用。然而，这些研究有两个关键的遗漏。首先，临床分离株的R基因代表了现有R基因多样性的一小部分。现在很清楚，抗生素耐药性早于人类介导的抗生素使用，同样清楚的是，对于人类发现，设计或开发的每一种药物，几乎可以肯定的是，微生物已经拥有防御机制，并且该机制转移到人类病原体只是时间问题。如果我们要成功地规划抗菌策略，对现有耐药机制的多样性有更全面的了解至关重要。其次，这些研究忽视了细菌及其耐药基因在自然界中所经历的复杂的生态和进化压力（除了人类介导的抗生素使用所造成的压力之外）。这些信息对于合理治疗方法的发展至关重要。本研究的目的是探索和对比肠道细菌自然和临床群体中抗生素耐药性的演变，并将这些数据应用于旨在开发更有效抗生素疗法的努力。我们在这里提议对自然细菌群体中的抗生素耐药性演变进行首次“全面”调查。使我们的研究全面的是对抗生素耐药表型，基因型，遗传变异和分歧水平，耐药相关健身效果的估计以及使用这些数据为现有抗生素治疗提供信息，并有助于设计更合理或新颖的治疗方法。

DESCRIPTION (provided by applicant): The development and spread of bacterial antibiotic resistance has emerged as a major public health concern. Pathogenic bacteria once easily controlled by antimicrobial drugs now frequently fail to respond to most antibiotics. Most research on the causes and consequences of antibiotic resistance focuses on clinical isolates of pathogenic bacteria, i.e. isolates from infected humans in hospitals. These studies reveal the diversity of resistance mechanisms and genes, the genetic details of how resistance spreads between bacterial lineages and provide estimates of the speed with which such spread occurs in hospital settings. Such clinically based studies play an essential role in efforts to track the course of antibiotic resistance evolution and suggest the priority of drug use for particular pathogens. However, these studies suffer from two critical omissions. First, R genes characterized from clinical isolates represent a small fraction of the existing diversity of R genes. It is now clear that antibiotic resistance predates the human mediated use of antibiotics and it is equally clear that for every drug humans discover, design or develop, it is almost certainly the case that microbes already possess a defensive mechanism and it is only a matter of time before that mechanism is transferred to a human pathogen. It is critical to have a more complete understanding of the diversity of existing resistance mechanisms if we are to successfully plan antimicrobial strategies. Second, these studies ignore the complex ecological and evolutionary pressures that bacteria and their resistance genes experience in nature (in addition to those resulting from human-mediated antibiotic use). This information is critical to the development of rational treatment therapies. The goal of this research is to explore and contrast the evolution of antibiotic resistance in natural and clinical populations of enteric bacteria and to apply these data to efforts aimed at the development of more effective antibiotic therapies. We propose here the first "comprehensive" survey of antibiotic resistance evolution in natural populations of bacteria. What makes our study comprehensive is the combined focus on antibiotic resistance phenotypes, genotypes, levels of genetic variation and divergence, estimates of resistance-associated fitness effects and the use of these data to inform existing antibiotic therapies and contribute to the design of more rational or novel therapies.