Dynamic energy budget approach to evaluate antibiotic effects on biofilms

Thumbnail Image
Full text at PDC
Publication Date
Advisors (or tutors)
Journal Title
Journal ISSN
Volume Title
Google Scholar
Research Projects
Organizational Units
Journal Issue
Quantifying the action of antibiotics on biofilms is essential to devise therapies against chronic infections. Biofilms are bacterial communities attached to moist surfaces, sheltered from external aggressions by a polymeric matrix. Coupling a dynamic energy budget based description of cell metabolism to surrounding concentration fields, we are able to approximate survival curves measured for different antibiotics. We reproduce numerically stratified distributions of cell types within the biofilm and introduce ways to incorporate different resistance mechanisms. Qualitative predictions follow that are in agreement with experimental observations, such as higher survival rates of cells close to the substratum when employing antibiotics targeting active cells or enhanced polymer production when antibiotics are administered. The current computational model enables validation and hypothesis testing when developing therapies.
[1] H.A. Abbas, F.M. Serry, E.M. EL-Masry, Combating Pseudomonas aeruginosa biofilms by potential biofilm inhibitors, Asian J. Res. Pharm. Sci. 2, 66-72, 2012. [2] M. Alipour, Z.E. Suntres, A. Omri, Importance of DNase and alginate lyase for enhancing free and liposome encapsulated aminoglycoside activity against Pseudomonas aeruginosa. J Antimicrob Chemother 64, 317-325, 2009. [3] H. Anwar, J.W. Costerton, Enhanced activity of combination of tobramycin and piperacillin for eradication of sessile biofilm cells of Pseudomonas aeruginosa, Antimicrob Agents Chemother 34, 1666-1671, 1990. [4] N. Bagge, M. Schuster, M. Hentzer, O. Ciofu, M. Givskov, E.P. Greenberg, et al, Pseudomonas aeruginosa biofilms exposed to imipenem exhibit changes in global genem expression and β-lactamase and alginate production. Antimicrob. Agents Chemother. 48, 1175-1187, 2004. [5] D. de Beer, P. Stoodley, F. Roe, Z. Lewandowski, Effects of biofilm structure on oxygen distribution and mass transport, Biotechnol Bioeng 43, 1131-1138, 1994. [6] A. Brooun, S. Liu, K. Lewis, A dose-response study of antibiotic resistance in Pseudomonas Aeruginosa biofilms, Antimicrob. Agents Chemother. 44, 640-646, 2000. [7] L. Chai, H. Vlamakis and R. Kolter, Extracellular signal regulation of cell differentiation in biofilms, MRS Bulletin 36, 374-379, 2011. [8] D.G. Davies, M.R. Parsek, J.P. Pearson, B.H. Iglewski, J.W. Costerton, E.P. Greenberg, The involvement of cell-to-cell signals in the development of a bacterial biofilm, Science 280, 295-298, 1998. [9] D. Davies, Understanding biofilm resistance to antibacterial agents, Nature Reviews 2, 114-122, 2003. [10] D.R. Espeso, A. Carpio, B. Einarsson, Differential growth of wrinkled biofilms, Phys. Rev E 91, 022710, 2015. [11] D.R. Espeso, A. Carpio, E. Martinez-Garcia, V. de Lorenzo, Stenosis triggers spread of helical Pseudomonas biofilms in cylindrical flow systems, Scientific Reports 6, 27170, 2016. [12] M. A. A. Grant, B.Waclaw, R. J. Allen, and P. Cicuta, The role of mechanical forces in the planar-to-bulk transition in growing Escherichia coli microcolonies, J. R. Soc. Interface 11, 20140400, 2014. [13] B. Halan, A. Schmid, K. Buehler, Real-time solvent tolerance analysis of Pseudomonas sp. strain VLB120C catalytic biofilms, Appl. Env. Microbiol. 77, 1563-1571, 2011. [14] M. Hendrata, B. Birnir, Dynamic energy budget driven fruiting body formation in myxobacteria, Physical Review E 81, 061902, 2010. [15] M. Hentzer, K. Riedel, T.B. Rasmussen, A. Heydorn, J.B. Andersen, M.R. Parsek, S.A. Rice, L. Eberl, S. Molin, N. Høiby, S. Kjelleberg, M. Givskov, Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound, Microbiology 148, 87-102, 2002. [16] N. Høiby, T. Bjarnsholt, M. Givskov, S. Molin, O. Ciofu, Antibiotic resistance of bacterial biofilms, International Journal of antimicrobial agents, Review, 322-332, 2010. [17] H. Ishida, Y. Ishida, Y. Kurosaka, T. Otani, K. Sato, H. Kobayashi, In vivo and in vitro activities of levofloxacin against biofilm producing Pseudomonas aeruginosa, Antimicrob. Agents Chemother. 42, 1641-1645, 1998. [18] R. Jaramayan, Antibiotic resistance: an overview of mechanisms and a paradigm shift, Current Science 96, 1475-1484, 2009. [19] A. Kim, C.A. Sutherland, J.L. Kuti, D.P. Nicolau, Optimal dosing of piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous Infusion? Pharmacotherapy 27, 1490-1497, 2007. [20] T. Klanjscek, R.M. Nisbet, J.H. Priester, P.A. Holden, Modeling physiological processes that relate toxicant exposure and bacterial population dynamics, PLOS One 7, e26955, 2012. [21] T. Klanjscek, R.M. Nisbet, J.H. Priester, P.A. Holden, Dynamic energy budget approach to modeling mechanisms of CdSe quantum dot toxicity, Ecotoxicology 22, 319-330, 2013. [22] S.A.L.M. Kooijman, Dynamic energy budget theory for metabolic organization, Cambridge University Press, 2008 [23] L. A. Lardon, B. V. Merkey, S. Martins, A. D¨otsch, C. Picioreanu, J. U. Kreft, B. F. Smets, iDynoMiCS: next generation individual-based modelling of biofilms, Environ. Microbiol. 13, 241624-24, 2011. [24] C. S. Laspidou and B. E. Rittmann, Modeling the development of biofilm density including active bacteria, inert biomass, and extracellular polymeric substances, Water Res. 38, 3349-3361, 2004. [25] XZ Li, D Ma, DM Livermore, H Nikaido, Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to beta-lactam resistance, Antimicrob. Agents Chemother 38, 1742-1752, 1994. [26] O. Lomovskaya, M.S. Warren, A. Lee, J. Galazzo, R. Fronko, M. Lee, J. Balis, D. Cho, S. Chamberland, T. Renau, R. Leger, S. Hecker, W. Watkins, K. Hoshino, H. Ishida, V.J. Lee, Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy, Antimicrob. Agents Chemother. 45, 105-116, 2001. [27] A. Mahamoud, J. Chevalier, S. Alibert-Franco, W.V. Kern, J.M. Page, Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy, J. Antimicrob. Chemother. 59, 1223-1229, 2007. [28] L.F. Mandsberg, O. Ciofu, N. Kirby, L.E. Christiansen, H.E. Poulsen, N. Høiby, Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system, Antimicrob. Agents Chemother. 53, 2483-2491, 2009. [29] K.C. Marshall, Biofilms: an overview of bacterial adhesion, activity, and control at surfaces, ASM News 58, 202-207, 1992. [30] K. Nagano, H. Nikaido, Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli, Proc. Nat. Acad. Sc. 106, 5854-5858, 2009. [31] National Nosocomial Infections Surveillance System. National nosocomial infections surveillance (NNIS) system report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 32, 470-485, 2004. [32] W.W. Nichols, M.J. Evans, M.P. Slack, H.L. Walmsley, The penetration of antibiotics into aggregates of mucoid and non-mucoid Pseudomonas aeruginosa. J Gen. Microbiol. 135, 1291-1303, 1989. [33] J.A. Robinson, M.G. Trulear, W.G. Characklis, Cellular reproduction and extracellular polymer formation by Pseudomonas aeruginosa in continuous culture, Biotech. Bioeng. XXVI, 1409-1417, 1984. [34] P.S. Stewart, Biofilm accumulation model that predicts antibiotic resistance of Pseudomonas aeruginosa biofilms, Antimicrob. Agents Chemother. 38, 1052-1057, 1994. [35] P.S. Stewart, J.W. Costerton, Antibiotic resistance of bacteria in biofilms, Lancet 358, 135-138, 2001. [36] P.S. Stewart, Mechanisms of antibiotic resistance in bacterial biofilms, Int. J. Med. Microbiol. 292, 107-113, 2002. [37] P.W. Stone, Economic burden of healthcare-associated infections: An American perspective, Expert. Rev. Pharmacoeconomics Outcomes Res. 9, 417-422, 2009. [38] T. Storck, C. Picioreanu, B. Virdis, and D. J. Batstone, Variable cell morphology approach for individual-based modeling of microbial communities, Biophys. J. 106, 2037-2048, 2014. [39] K. Vickery, H. Hu, A.S. Jacombs, D.A. Bradshaw, A.K. Deva, A review of bacterial biofilms and their role in device-associated infection, Healthcare Infection 18, 61-66, 2013. [40] M.C. Walters, F. Roe, A. Bugnicourt, M.J. Franklin, P.S. Stewart, Contributions of antibiotic penetration, oxygen limitation, and low metabolic activity to tolerance of Pseudomonas aeruginosa biofilms to ciprofloxacin and tobramycin, Antimicrob. Agents Chemother. 47, 317-323, 2003. [41] E. Werner, F. Roe, A. Bugnicourt, M.J. Franklin, A. Heydorn, S. Molin, B. Pitts, P.S. Stewart, Stratified growth in Pseudomonas Aeruginosa biofilms, Appl. Environ. Microbiol. 70, 6188-6196, 2004.