Antibiotic Susceptibility of Bacteria in Biofilms

描述（由申请人提供）：当细菌附着在表面并作为生物膜生长时，它们就不会被抗生素杀死。生物膜的形成越来越被认为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生物膜降低抗生素杀伤敏感性的第一个综合现象学模型来补充正在进行的生物膜抗生素耐药性的实验研究。现有的生物膜发展的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延迟、由于局部营养物质消耗而导致部分生物膜代谢活性或生长降低、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为类似于孢子形成的休眠持续状态。基于生物膜作为粘弹性流体的力学分析，通过开发细胞从生物膜中释放的数学表达式，该模型将得到改进。最后，将模型结果与实验数据进行对比。实验将在铜绿假单胞菌实验系统中进行，以测量对抗生素治疗的时空响应，包括杀死和脱离，并将这些结果与数学模型的输出进行比较。在了解生物膜感染在面对抗生素化疗时顽固的持久性方面，进展出奇地缓慢。这种建模工作将通过集成许多必须考虑的组成现象来加速这一工作，并作为必须沟通以解决这一问题的不同学科之间对话的媒介。该模型最终将成为一种工具，用于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，并确定最佳抗生素剂量方案。该项目将为三位参与的研究生提供丰富的跨学科培训经验。

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.