This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roberts, M. E. Articles by Stewart, P. S. Search for Related Content PubMed PubMed Citation Articles by Roberts, M. E. Articles by Stewart, P. S.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 2004, p. 48-52, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.48-52.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Modeling Antibiotic Tolerance in Biofilms by Accounting for Nutrient Limitation

Center for Biofilm Engineering and Department of Chemical and Biological Engineering, Montana State University—Bozeman, Bozeman, Montana 59717-3980

Received 13 January 2003/ Returned for modification 8 July 2003/ Accepted 6 October 2003

A mathematical model of biofilm dynamics was used to investigate the protection from antibiotic killing that can be afforded to microorganisms in biofilms based on a mechanism of localized nutrient limitation and slow growth. The model assumed that the rate of killing by the antibiotic was directly proportional to the local growth rate. Growth rates in the biofilm were calculated by using the local concentration of a single growth-limiting substrate with Monod kinetics. The concentration profile of this metabolic substrate was calculated by solving a reaction-diffusion problem. The model predicted the following features: stratified patterns of growth with zones of no growth in the biofilm interior, slow killing of biofilm microorganisms that was further retarded as the initial biofilm thickness increased, nonuniform spatial patterns of killing inside the biofilm, biofilm killing rates that decrease in a nonlinear way as the concentration of the growth-limiting substrate feeding the biofilm is decreased, and heightened tolerance when external mass transfer resistance is manifested. This modeling study also provides motivation for further investigation of a hypothetical cell state in which damaged cells score as nonviable but continue to consume substrate. The existence of such a cell state can further retard biofilm killing, according to the simulations. The results support the important contributions of nutrient limitation and slow growth to the antibiotic tolerance of microorganisms in biofilms.

This article has been cited by other articles:

• Klapper, I., Gilbert, P., Ayati, B. P., Dockery, J., Stewart, P. S. (2007). Senescence can explain microbial persistence. Microbiology 153: 3623-3630 [Abstract] [Full Text]  
• Patrauchan, M. A., Sarkisova, S. A., Franklin, M. J. (2007). Strain-specific proteome responses of Pseudomonas aeruginosa to biofilm-associated growth and to calcium. Microbiology 153: 3838-3851 [Abstract] [Full Text]  
• Garo, E., Eldridge, G. R., Goering, M. G., Pulcini, E. D., Hamilton, M. A., Costerton, J. W., James, G. A. (2007). Asiatic Acid and Corosolic Acid Enhance the Susceptibility of Pseudomonas aeruginosa Biofilms to Tobramycin. Antimicrob. Agents Chemother. 51: 1813-1817 [Abstract] [Full Text]  
• Chambless, J. D., Hunt, S. M., Stewart, P. S. (2006). A three-dimensional computer model of four hypothetical mechanisms protecting biofilms from antimicrobials.. Appl. Environ. Microbiol. 72: 2005-2013 [Abstract] [Full Text]  
• Roberts, M. E., Stewart, P. S. (2005). Modelling protection from antimicrobial agents in biofilms through the formation of persister cells. Microbiology 151: 75-80 [Abstract] [Full Text]