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）：当细菌附着在表面并生长为生物膜时，它们会受到抗生素的保护而免遭杀死。人们越来越认识到生物膜的形成是各种感染持续存在的一个因素。该项目的目标是通过开发第一个全面的生物膜现象学模型来补充正在进行的生物膜中抗生素耐药性的实验研究，该模型降低了抗生素杀死的敏感性。现有的生物膜发育数学模型将扩展到包括四种假设的保护机制。这些机制解决了抗生素渗透迟缓、由于局部营养耗尽而导致的生物膜部分代谢活动或生长减少、一些生物膜细菌的应激反应激活以及一些生物膜细胞分化成类似于孢子形成的休眠持续状态。该模型将通过基于对粘弹性流体的生物膜的机械分析来开发细胞从生物膜中释放的数学表达式来改进。最后，模型结果将与实验数据进行比较。将进行实验来测量铜绿假单胞菌实验系统中抗生素治疗的时空反应，包括杀死和分离，并将这些结果与数学模型的输出进行比较。面对抗生素化疗，了解生物膜感染顽固存在的进展出人意料地缓慢。这种建模工作将通过整合必须考虑的许多构成现象来加速这一工作，并作为必须沟通以解决该问题的不同学科之间对话的工具。该模型最终将成为研究假设的耐药机制的后果、设计实验来测试这些机制、确定新的治疗策略以及确定最佳抗生素剂量方案的工具。该项目将为参与的三名研究生提供丰富的跨学科培训经验。