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MBio. 2019 Jan 29;10(1). pii: e02460-18. doi: 10.1128/mBio.02460-18.

Simulating Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing Model.

Author information

Department of Microbiology, Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain.
Department of Information Systems and Computation (DSIC), Universitat Politècnica de València, Valencia, Spain.
Network Research Center for Epidemiology and Public Health (CIBER-ESP), Madrid, Spain.
Biotechvana, Paterna, Valencia, Spain.
Antibiotic Resistance and Bacterial Virulence Unit (HRYC-CSIC), Superior Council of Scientific Research (CSIC), Madrid, Spain.
Integrative Systems Biology Institute, University of Valencia and Spanish Research Council (CSIC), Paterna, Valencia, Spain.
Foundation for the Promotion of Sanitary and Biomedical Research in the Valencian Community (FISABIO), Valencia, Spain.
Bioinformatics Support Unit, IRYCIS, Madrid, Spain.
Biotechvana, Paterna, Valencia, Spain
Department of Microbiology, Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain


Membrane computing is a bio-inspired computing paradigm whose devices are the so-called membrane systems or P systems. The P system designed in this work reproduces complex biological landscapes in the computer world. It uses nested "membrane-surrounded entities" able to divide, propagate, and die; to be transferred into other membranes; to exchange informative material according to flexible rules; and to mutate and be selected by external agents. This allows the exploration of hierarchical interactive dynamics resulting from the probabilistic interaction of genes (phenotypes), clones, species, hosts, environments, and antibiotic challenges. Our model facilitates analysis of several aspects of the rules that govern the multilevel evolutionary biology of antibiotic resistance. We examined a number of selected landscapes where we predict the effects of different rates of patient flow from hospital to the community and vice versa, the cross-transmission rates between patients with bacterial propagules of different sizes, the proportion of patients treated with antibiotics, and the antibiotics and dosing found in the opening spaces in the microbiota where resistant phenotypes multiply. We also evaluated the selective strengths of some drugs and the influence of the time 0 resistance composition of the species and bacterial clones in the evolution of resistance phenotypes. In summary, we provide case studies analyzing the hierarchical dynamics of antibiotic resistance using a novel computing model with reciprocity within and between levels of biological organization, a type of approach that may be expanded in the multilevel analysis of complex microbial landscapes.IMPORTANCE The work that we present here represents the culmination of many years of investigation in looking for a suitable methodology to simulate the multihierarchical processes involved in antibiotic resistance. Everything started with our early appreciation of the different independent but embedded biological units that shape the biology, ecology, and evolution of antibiotic-resistant microorganisms. Genes, plasmids carrying these genes, cells hosting plasmids, populations of cells, microbial communities, and host's populations constitute a complex system where changes in one component might influence the other ones. How would it be possible to simulate such a complexity of antibiotic resistance as it occurs in the real world? Can the process be predicted, at least at the local level? A few years ago, and because of their structural resemblance to biological systems, we realized that membrane computing procedures could provide a suitable frame to approach these questions. Our manuscript describes the first application of this modeling methodology to the field of antibiotic resistance and offers a bunch of examples-just a limited number of them in comparison with the possible ones to illustrate its unprecedented explanatory power.


antibiotic resistance; computer modeling; mathematical modeling; membrane computing; multilevel

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