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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067245-03
Application #
6784670
Study Section
Special Emphasis Panel (ZGM1-CMB-0 (MB))
Program Officer
Anderson, James J
Project Start
2002-08-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$199,800
Indirect Cost
Name
Montana State University Bozeman
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
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Stewart, Philip S; Franklin, Michael J (2008) Physiological heterogeneity in biofilms. Nat Rev Microbiol 6:199-210
Klapper, I; Gilbert, P; Ayati, B P et al. (2007) Senescence can explain microbial persistence. Microbiology 153:3623-30
Alpkvist, E; Klapper, I (2007) Description of mechanical response including detachment using a novel particle model of biofilm/flow interaction. Water Sci Technol 55:265-73
Chambless, Jason D; Stewart, Philip S (2007) A three-dimensional computer model analysis of three hypothetical biofilm detachment mechanisms. Biotechnol Bioeng 97:1573-84
Alpkvista, Erik; Klapper, Isaac (2007) A multidimensional multispecies continuum model for heterogeneous biofilm development. Bull Math Biol 69:765-89
Klapper, I; Dockery, J (2006) Role of cohesion in the material description of biofilms. Phys Rev E Stat Nonlin Soft Matter Phys 74:031902
Chambless, Jason D; Hunt, Stephen M; Stewart, Philip S (2006) A three-dimensional computer model of four hypothetical mechanisms protecting biofilms from antimicrobials. Appl Environ Microbiol 72:2005-13
Borriello, Giorgia; Richards, Lee; Ehrlich, Garth D et al. (2006) Arginine or nitrate enhances antibiotic susceptibility of Pseudomonas aeruginosa in biofilms. Antimicrob Agents Chemother 50:382-4

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