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: 10583502
• 负责人: Dan Andersson
• 金额: $ 37.89万
• 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/10583502
• 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; Modeling; Pap smear; Pharmaceutical Preparations; Phenotype; Physiological; Population; Population Analysis; Predisposition; Process; Property; Research Project Grants; Resistance; Sequence Analysis; Signal Transduction; Sweden; Treatment Failure; Treatment outcome; Work; bacteria classification; bacterial resistance; 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 了解抗生素耐药机制对于设计新方法和疗法至关重要 对抗耐药细菌。异抗性 (HR) 是一种细菌表型，其中分离株含有 与主要细胞群相比，抗生素耐药性显着增加的细胞亚群。 许多种类的细菌和几乎所有类别的抗生素都表现出这种形式的表型抗性，并且存在 来自体外实验、数学模型、动物感染模型和临床研究的证据表明 耐药亚群会在抗生素暴露期间丰富并导致治疗失败。最近的研究 表明 HR 中的耐药表型在大多数情况下是不稳定的并且在没有抗生素的情况下 压力会迅速恢复到敏感性。不稳定的主要原因之一是遗传因素的发生 不同类型基因的不稳定串联基因扩增，当存在于环境中时可能导致耐药性 拷贝数增加（例如，通常以低水平表达的真正抗性基因、外排 泵）。由于不稳定、低频和瞬态特性，检测和研究这些现象具有挑战性。 亚群体和临床微生物学环境中，这通常会导致明确分类的困难 细菌敏感或耐药，这可能导致潜在的治疗失败。为了便于改进 HR感染的治疗和检测，我们需要详细了解其背后的机制和 耐药亚群形成、维持并退回到基线的动态 在没有抗生素的情况下的频率。具体来说，我们会问：关键的遗传、生理和 控制耐药亚群产生的环境过程和信号，以及随后， 我们是否以及如何修改和干扰它们。为了解决这些问题，我们将使用临床分离物 肠杆菌科（大肠杆菌、肺炎克雷伯菌和肠杆菌属）和鲍曼不动杆菌。 在基本层面上，这项工作将显着拓宽我们对以下方面的理解：（i） 细胞亚群的产生可以影响细菌群体的行为和进化，（ii）如何 HR 由 CNV 产生，(iii) CNV 的机制和动态，以及 (iv) 如何根据 CNV 预测 HR 全基因组测序数据。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缓解 它在临床环境中的影响，从而改善抗生素治疗的结果。