Project 1: Mechanisms, Dynamics, and Prediction of Heteroresistance

项目1：异阻性的机制、动力学和预测

• 批准号: 10170970
• 负责人: Dan Andersson
• 金额: $ 34.79万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170970
• 关键词: Acinetobacter baumannii; Acute; Address; Aftercare; Algorithms; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Back; Bacteria; Biological; Cells; Clinical; Clinical Microbiology; Clinical Research; Collection; Copy Number Polymorphism; Data; Detection; Enterobacter; Enterobacteriaceae; Escherichia coli; Evolution; Exhibits; Frequencies; Gene Amplification; Generations; Genes; Genetic; Genome; Gram-Negative Bacteria; In Vitro; Infection; Interdisciplinary Study; Intermediate resistance; Klebsiella pneumoniae; Lead; Modeling; Pharmaceutical Preparations; Phenotype; Physiological; Population; Population Analysis; Predisposition; Process; Property; Research Project Grants; Resistance; Sequence Analysis; Signal Transduction; Sweden; Treatment Failure; Treatment outcome; Work; bacterial resistance; base; behavior influence; clinically relevant; combat; cost; design; efflux pump; experimental study; fitness; genetic analysis; genetic testing; genome sequencing; improved; mathematical model; novel strategies; novel therapeutics; pressure; recurrent infection; resistance gene; resistance mechanism; screening; tool; trait; whole genome

ABSTRACT Understanding antibiotic resistance mechanisms is critical to designing novel approaches and therapeutics to combat resistant bacteria. Heteroresistance (HR) is a bacterial phenotype in which an isolate contains a subpopulation of cells that show a substantial increase in antibiotic resistance compared to the main population. Many species of bacteria and nearly all classes of antibiotics exhibit this form of phenotypic resistance and there is evidence from in vitro experiments, mathematical modeling, animal infection models and clinical studies that the resistant subpopulations can enrich during antibiotic exposure and lead to treatment failure. Recent studies show that the resistance phenotype in HR is in the majority of cases unstable and in the absence of antibiotic pressure it rapidly reverts to susceptibility. One major reason for the instability is the occurrence of genetically unstable tandem gene amplifications of different types of genes that can cause resistance when present at an increased copy number (e.g., bona fide resistance genes that are normally expressed at low levels, efflux pumps). Due to the instability, low frequency and transient character, it is challenging to detect and study these subpopulations and in a clinical microbiology setting this often leads to difficulties in unambiguously classifying bacteria as susceptible or resistant, which can lead to potential treatment failures. To facilitate the improved treatment and detection of HR infections, we need to understand in detail the underlying mechanisms and dynamics by which the resistant sub-populations form, are maintained and recede back to their baseline frequency in the absence of antibiotic. Specifically, we will ask: what are the key genetic, physiological and environmental processes and signals that govern the generation of resistant sub-populations and subsequently, if and how we may modify and interfere with them. To address these questions, we will use clinical isolates of Enterobacteriaceae (E. coli, K. pneumoniae and Enterobacter spp) and A. baumannii. At a basic level, this work will significantly broaden our understanding of (i) how traits exhibited by a subpopulation of cells is generated and can influence behavior and evolution of bacterial populations, (ii) how HR is generated by CNV, (iii) the mechanisms and dynamics of CNV and (iv) how HR may be predicted from whole genome sequencing data. This will, in the long-term, provide us with better tools to identify HR and mitigate its effects in clinical settings and, thereby, improve antibiotic treatment outcome.

抽象的 了解抗生素抗性机制对于设计新方法和治疗剂至关重要 抗战斗细菌。异耐（HR）是一种细菌表型，其中分离物包含A 与主要种群相比，细胞的亚群显示出抗生素耐药性的大幅增加。 许多细菌和几乎所有类别的抗生素都表现出这种表型抗性，那里 是体外实验，数学建模，动物感染模型和临床研究的证据 抗性亚群可以在抗生素暴露期间富集并导致治疗衰竭。最近的研究 表明HR中的抗性表型在大多数情况下不稳定，并且在没有抗生素的情况下 压力迅速恢复为敏感性。不稳定性的主要原因是遗传上的发生 不同类型基因的不稳定串联基因扩增，这些基因可能在存在于 拷贝数增加（例如，善意的抗性基因，通常在低水平上表达 泵）。由于不稳定，低频和瞬态特征，检测和研究这些 亚群和临床微生物学设置，这通常会导致明确分类的困难 细菌是易感或抗性的，这可能导致潜在的治疗失败。促进改进 人力资源感染的治疗和检测，我们需要详细了解潜在机制和 保持抗性子群的形成，维持并退回其基线的动力学 在没有抗生素的情况下频率。具体来说，我们会问：什么是关键的遗传，生理和 环境过程和信号，这些过程控制着抗性亚种群的产生，然后 如果以及我们如何修改和干扰它们。为了解决这些问题，我们将使用 肠杆菌科（E. Coli，K。Pneumoniae和Enterobacter spp）和A. baumannii。 在基本层面上，这项工作将大大扩大我们对（i）一个特征的理解 产生细胞的亚群，可以影响细菌群体的行为和进化，（ii） HR由CNV，（iii）CNV的机理和动力学产生，以及（iv）如何​​从中预测HR 整个基因组测序数据。从长远来看，这将为我们提供更好的工具来识别人力资源并减轻 它在临床环境中的影响，从而改善抗生素治疗结果。