Metabolic heterogeneity and antibiotic susceptibility in biofilms

生物膜中的代谢异质性和抗生素敏感性

• 批准号: 7890252
• 负责人: AARON I PACKMAN
• 金额: $ 37.94万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890252
• 关键词: Address; Affect; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Antimicrobial Effect; Antimicrobial susceptibility; Catheters; Cell Death; Cells; Chemicals; Communities; Complex; Confocal Microscopy; Coupled; Coupling; Development; Devices; Dyes; Effectiveness; Elements; Environment; Growth; Heterogeneity; Implant; In Situ; Infection; Measurement; Measures; Medical Device; Metabolic; Methods; Microbial Biofilms; Modeling; Mono-S; Morphology; Organism; Orthopedics; Oxygen; Pattern; Predisposition; Process; Relative (related person); Reporter; Simulate; Site; Staining method; Stains; Structure; Surface; System; Time; Velocimetries; Work; antimicrobial; antimicrobial drug; base; design; fluorophore; implantable device; improved; insight; killings; microbial community; model development; novel; particle; pathogen; protective effect; public health relevance; research study; simulation; tool

DESCRIPTION (provided by applicant): Biofilms are microbial communities that grow attached to a surface. Biofilm-based infections occur frequently, and biofilm growth on indwelling devices is very difficult to eradicate. Low rates of antibiotic transport within biofilms, protective effects of the biofilm matrix, and low rates of metabolic activity within the biofilm interior have all been found to contribute to the persistence of these infections, but there is currently little understanding of the processes responsible for these effects. While spatial heterogeneity in biofilms is clearly important to selection of therapy for biofilm-based infections, little information is available on the way in which local environmental conditions influence the development of spatial patterns in biofilms, and hence how the effectiveness of antibiotics varies depending on the body site and type of indwelling device. We hypothesize that spatial patterns of metabolic activity within a biofilm are influenced by spatial patterns in the flow environment, and that these interactions cause biofilm complexity to increase over time. We also hypothesize that the flow environment affects biofilm antimicrobial susceptibility not only by influencing delivery of antimicrobials to cells within the biofilm but also by dictating metabolic gradients within the community. We propose to address these hypotheses through the following specific aims. Aim 1: Observe growth of mono- species biofilms in a planar flow cell in order to assess changes in biofilm morphology, transport patterns, and metabolic activity with increasing spatial variability in environmental flow conditions. Aim 2: Observe the effectiveness of antibiotic treatment in eradicating biofilms having different degrees of spatial complexity, and relate the distribution of local killing efficiency to spatial patterns in transport conditions and metabolic activity. Aim 3: Develop an improved numerical model to allow quantitative analysis of the effects described above. Aim 4: Use the model to clarify multi-scale flow-biofilm interactions, and particularly to evaluate the key features that contribute to the survival of subpopulations of cells in biofilms under antibiotic treatment. We propose to achieve these aims by using a combination of novel experiments and numerical modeling. We will conduct experiments on biofilm growth and treatment in a new experimental system that provides the ability to impose a precisely controlled degree of spatial variability in inflow and outflow patterns. Biofilm growth, changes in flow and oxygen distributions, transport of antibiotic, and the resulting cell death will all be observed directly in situ. We will utilize these new and unique observations to support development of a new numerical model for biofilm development, which will subsequently be used to simulate the effectiveness of antibiotic treatment in eradicating biofilms under different local growth conditions. This combination of measurements and modeling will provide unique insight into the way in which biofilm growth interacts with and modifies the external flow, and ultimately how this complex interaction controls the overall formation of the biofilm and the effects of introduced antimicrobial agents on cells residing in the biofilm matrix. PUBLIC HEALTH RELEVANCE: Metabolic heterogeneity and antibiotic susceptibility in biofilms Summary Narrative Biofilm-based infections of inserted and implanted medical devices such as catheters, neurosurgical devices, and orthopedic devices are difficult to treat. Low rates of antibiotic transport within biofilms, protective effects of the biofilm matrix, and low rates of metabolic activity within the biofilm interior have all been found to contribute to the persistence of these infections, but there is currently little understanding of the processes responsible for these effects. The proposed work will advance understanding of how local environmental conditions influence biofilm growth, and will develop improved tools for assessing the effectiveness of antibiotics against biofilm-based infections.

描述（由申请人提供）：生物膜是在表面附着的微生物群落。基于生物膜的感染经常发生，并且很难消除留置器件上的生物膜生长。在生物膜内的抗生素转运率低，生物膜基质的保护作用以及生物膜内部内部内部内部的代谢活性率低都会导致这些感染的持续性，但目前对这些过程的理解很少效果。虽然生物膜中的空间异质性对于选择基于生物膜的感染的治疗显然很重要，但几乎没有有关局部环境条件影响生物膜中空间模式发展的方式的信息，因此抗生素的有效性取决于抗生素的有效性各不相同。车身站点和住宅设备的类型。我们假设生物膜内代谢活性的空间模式受流动环境中的空间模式的影响，并且这些相互作用会导致生物膜复杂性随时间增加。我们还假设流动环境不仅会影响生物膜抗菌敏感性，这不仅是通过影响生物膜内细胞的递送，还通过决定社区内的代谢梯度。我们建议通过以下特定目标解决这些假设。 AIM 1：观察平面流动细胞中单种生物膜的生长，以评估生物膜形态，传输模式和代谢活性的变化，并在环境流条件下的空间变异性增加。目标2：观察抗生素处理在消除具有不同程度的空间复杂性的生物膜中的有效性，并将局部杀伤效率的分布与传输条件和代谢活性中的空间模式联系起来。 AIM 3：开发改进的数值模型，以允许对上述效果进行定量分析。 AIM 4：使用该模型阐明多尺度流动性胶片相互作用，尤其是评估在抗生素处理下有助于生物膜中细胞亚植物生存的关键特征。我们建议通过结合新实验和数值建模来实现这些目标。我们将在新的实验系统中对生物膜生长和治疗进行实验，该实验能够在流入和流出模式中施加精确控制的空间变化程度。生物膜生长，流量和氧分布的变化，抗生素的转运以及所得的细胞死亡将直接观察到原位。我们将利用这些新的独特的观察结果来支持生物膜开发的新数值模型的开发，随后将用于模拟抗生素处理在不同局部生长条件下消除生物膜中的有效性。测量和建模的这种组合将为生物膜生长与外部流动相互作用并修改外部流动的方式提供独特的见解，并最终如何控制这种复合物的整体形成生物膜的整体形成以及引入的抗菌素对驻留在细胞中的影响。生物膜基质。 公共卫生相关性：生物膜中的代谢异质性和抗生素易感性汇总的叙事叙事生物膜基于插入和植入的医疗设备的感染，例如导管，神经外科手术器件和矫形器件。在生物膜内的抗生素转运率低，生物膜基质的保护作用以及生物膜内部内部内部内部的代谢活性率低都会导致这些感染的持续性，但目前对这些过程的理解很少效果。拟议的工作将提高人们对局部环境状况如何影响生物膜生长的理解，并将开发改进的工具，以评估抗生素针对基于生物膜的感染的有效性。