Evolutionary paths toward intrinsic antibiotic resistance

内在抗生素耐药性的进化路径

• 批准号: 8733070
• 负责人: Alexandra Nogueira Ketcham
• 金额: $ 4.27万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733070
• 关键词: Aminoglycoside Antibiotics; Anabolism; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Area; Attention; Bacteria; Bacterial Infections; Biological Assay; Cataloging; Catalogs; Cause of Death; Cereals; Clinical; Complex; Cost Analysis; Coupled; Data; Development; Diagnostic; Drug Targeting; Escherichia coli; Evolution; Folic Acid; Foundations; Future; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic Epistasis; Genome; High-Throughput Nucleotide Sequencing; Incidence; Individual; Infection; Knock-out; Laboratories; Learning; Libraries; Maps; Measures; Methods; Microbe; Minimum Inhibitory Concentration measurement; Molecular Profiling; Morbidity - disease rate; Mutation; Pathway interactions; Pharmaceutical Preparations; Physiological; Process; Regulatory Pathway; Research; Research Personnel; Resistance; Resistance Process; Resistance development; Signal Pathway; Societies; Sorting - Cell Movement; Treatment Protocols; Work; antimicrobial; bacterial resistance; beta-Lactams; biological adaptation to stress; combat; cost; dosage; drug discovery; fitness; genetic linkage analysis; global health; information gathering; inhibitor/antagonist; microorganism; mortality; next generation; novel; novel diagnostics; novel therapeutics; public health relevance; research study; resistance mechanism; resistant strain; response; treatment strategy; trend

DESCRIPTION (provided by applicant): Widespread use or misuse of antibiotics has spurred evolutionarily adaptations that enable bacteria to survive many of our most powerful drugs. While existing antimicrobials are losing their effect, there has been in recent years a steep decline in the development of new drugs. If this trend continues, the drugs we have to combat resistant microorganisms will soon be depleted. The growing incidence of illness and death caused by antibiotic resistant infections, coupled with the cost that society has to pay for them, reflect our urgent need for new antibiotics that either block or circumvent resistance mechanisms, or attack new targets. We need a better understanding of the different ways in which resistance develops so that we can develop new methods to identify and counteract it. The research proposed here will provide a broader picture of the evolution of resistance and dissect the genetic mechanisms of its development. We plan to conduct laboratory evolution experiments in which we adapt E. coli to antibiotics from three commonly used classes and discern the mechanisms by which they develop resistance using high-¿throughput sequencing and whole genome linkage analysis. Once contributing loci are identified and validated, we will use global epistasis assays and transcriptome analysis to place them in the broader network context of specific signaling and regulatory pathways. We will classify these mutations in order to help simplify and untangle the magnitude and complexity of antibiotic-¿bacterial dynamics. Previous research suggests that clinical levels of antibiotic resistance may develop through the sequential accumulation of mutations of small individual effect. Understanding the order in which different mutations occur will give us information that may be useful for developing better diagnostics and in delaying the development of resistance. Throughout this research, special attention will be paid to the trajectory of resistance in the face of increasing drug dosage and also to associated fitness costs to the microorganism under other conditions. The ability of microbes to resist antibiotics often negatively impacts their fitness in the absence of treatment; however, mutations that confer resistance are often quickly followed by additional mutations elsewhere in the genome that compensate for these costs. Understanding the order in which different mutations occur will give us information about how strains become increasingly resistant. Also, since the fitness costs determine the strength of selection against resistant bacteria, analysis of these costs may inform novel treatment regimens. The aim of this research is to uncover new targets to combat resistance, new pathways that synergize with a particular antibiotic and, more broadly, to strengthen and enrich the underlying principles that will lay the foundation for the next generation of novel therapies, drug discovery, and diagnostics in the field.

描述（由适用提供）：宽度使用或错过抗生素具有进化适应性，使细菌能够在我们许多最强大的药物中生存。尽管现有的抗微生物正在失去其作用，但近年来，新药的发展急剧下降。如果这种趋势继续下去，我们必须将抗性微生物对抗的药物很快就会耗尽。抗生素耐药感染引起的疾病和死亡事件日益严格，再加上社会必须为其付出的代价 反映了我们迫切需要阻止或避免抗药机制或攻击新目标的新抗生素。我们需要更好地了解抵抗发展的不同方式，以便我们可以开发新的方法来识别和抵消它。这里提出的研究将为抗性的演变提供更广泛的了解，并剖析其发展的遗传机制。我们计划进行实验室进化实验，其中我们将大肠杆菌适应三个常用类别的抗生素，并辨别出使用高吞吐量测序和整个基因组链接分析的机制。一旦确定和验证了局部贡献，我们将使用全局的上静脉测定和转录组分析将它们置于特定信号传导和监管途径的更广泛的网络环境中。我们将对这些突变进行分类，以帮助简化和解开抗生素 - 细菌动力学的大小和复杂性。先前的研究表明，抗生素耐药性的临床水平可能通过依次的较小个体作用突变的顺序积累而发展。了解发生不同突变的顺序将为我们提供可能有助于开发更好的诊断和延迟阻力发展的信息。通过这项研究，面对增加的药物剂量，以及在其他条件下的微生物相关的适应性成本，将特别注意抗药性轨迹。微生物抵抗抗生素的能力通常会在没有治疗的情况下对其健康产生负面影响。但是，通常在基因组中其他地方的其他突变弥补这些成本的突变。了解发生不同突变的顺序将为我们提供有关菌株如何变得越来越抗性的信息。同样，由于健身成本决定了针对抗性细菌的选择强度，因此对这些成本的分析可能会为新的治疗方案提供依据。这项研究的目的是发现与特定抗生素协同作用的新目标，以加强和丰富将为下一代新的疗法，药物发现和该领域的诊断奠定基础的基本原则。