Antibiotic Susceptibility of Bacteria in Biofilms

生物膜中细菌的抗生素敏感性

• 批准号: 6784670
• 负责人: PHILIP S STEWART
• 金额: $ 19.98万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784670
• 关键词: Pseudomonas aeruginosa; adhesions; antibiotics; bacteria infection mechanism; biofilm; drug resistance; mathematical model

DESCRIPTION (provided by applicant): When bacteria attach to a surface and grow as a biofilm they are protected from killing by antibiotics. Biofilm formation is increasingly recognized as a factor in the persistence of varied infections. The goal of this project is to complement ongoing experimental investigations of antibiotic resistance in biofilms by developing the first comprehensive, phenomenological model of biofilm reduced susceptibility to killing by antibiotics. An existing mathematical model of biofilm development will be expanded to include four hypothesized protective mechanisms. These mechanisms address retarded antibiotic penetration, reduced metabolic activity or growth in parts of the biofilm due to local nutrient depletion, stress response activation by some biofilm bacteria, and differentiation of some biofilm cells into a dormant persister state analogous to spore formation. The model will be improved by developing mathematical expressions for the release of cells from the biofilm based on a mechanical analysis of the biofilm as a viscoelastic fluid. Finally, model results will be compared to experimental data. Experiments will be performed to measure spatio-temporal responses, including both killing and detachment, to antibiotic treatment in a P. aeruginosa experimental system, and these results will be compared with output of the mathematical model. Progress in understanding the stubborn persistence of biofilm infections in the face of antibiotic chemotherapy has been surprisingly slow. This modeling effort will accelerate this effort by integrating the many constituent phenomena that must be considered and serving as a vehicle for dialogue between the diverse disciplines that must communicate to solve this problem. The model will ultimately be a tool for investigating the consequences of hypothesized resistance mechanisms, designing experiments to test these mechanisms, identifying novel treatment strategies, and determining optimal antibiotic dosing protocols. This project will afford a rich interdisciplinary training experience for the three participating graduate students.

描述（由申请人提供）：当细菌附着在表面上并作为生物膜生长时，它们会免受抗生素的杀伤。生物膜形成越来越被认为是不同感染持续性的因素。该项目的目的是通过开发第一个全面的，现象学模型的生物膜模型来补充生物膜中抗生素耐药性的持续实验研究，从而降低了抗生素杀伤的易感性。现有的生物膜开发数学模型将扩展到包括四种假设的保护机制。这些机制解决了由于局部养分耗竭，某些生物膜细菌的应激反应激活以及某些生物膜细胞的胁迫反应激活以及将某些生物膜细胞的分化成与孢子形成的态度相似的态度。该模型将通过基于生物膜作为粘弹性流体的机械分析来开发数学表达式来从生物膜中释放细胞的数学表达式。最后，将将模型结果与实验数据进行比较。将进行实验，以测量铜绿假单胞菌实验系统中的抗生素处理，包括杀戮和脱离在内的时空反应，包括杀戮和脱离，并将这些结果与数学模型的输出进行比较。面对抗生素化学疗法的生物膜感染的顽固持续性的进展令人惊讶地缓慢。这项建模工作将通过整合必须考虑的许多组成现象来加速这一工作，并将其作为必须交流以解决这个问题的各种学科之间对话的工具。该模型最终将成为研究假设的抗性机制的后果，设计实验来测试这些机制，识别新型治疗策略并确定最佳抗生素剂量方案。该项目将为三个参与研究生提供丰富的跨学科培训经验。