Antibiotic Resistance Evolution Simulator

Quick start

(All interfaces can be navigated back and forward)

Steps for configuration of a P-system model

  1. Create a user account and log in ARES. If you have an already created user account just log in.

  2. Create an ECO membrane and give it a name and description using the tab “add ECO” in the interface ECO. Then select the model by clicking on its ID to skip to the next interface (ENVIRONMENTS).

  3. Within ENVIRONMENTS, click on the tab “Add environments” to define the number of P-regions you want to compute (representing physical compartments where different hosts spread). A table will appear for assigning name and ID to each P-region created. Then, click on the tab “Go to reservoirs at the bottom of the interface in order to access the next interface (RESERVOIRS).

  4. Within RESERVOIRS, click on the tab “Add reservoirs” to select which RS regions you want to compute in each P-membrane (representing physical compartments where different hosts spread). There are three types RS membranes:

    • Food supplier: introduces food into the environment membrane.
    • Water supplier: introduces water into the environment membrane.
    • Sewage: water-carried waste and faecal droppings.

    By clicking on the “Add reservoirs” tab a table will appear for selecting the RS membranes you want to be present in your P-system. Then go to the summary where P-membranes are listed and click on the “Assign” tab (in the column actions) of the first P-region listed to add any or all of the RS membranes within the selected P-region and click on “Save” button to make changes effective. You can add one, two or three types RS membranes to the selected P-membrane. Do this for all P-membranes. If you did everything right, you will see a set of blue boxes in the interface summary and within each P-region confirming that (and which) reservoirs have been added to each P-region. Then, click on the “Hosts” tab at the bottom of the interface to access the next interface (HOSTS).

  5. Within HOSTS introduce the number of H-membranes (host types/groups/species) you want to compute in your P-system using the “Add host type” tab. As in the previously explained interfaces, a table will appear for you to specify for each type an unique ID and a description. Click on “Save” and go to the P-membranes summary and click on the “Assign” tab of the first P-region listed. Another table will appear for you to select the H-membrane types you want to create in the selected P-region and assign each type of H-membrane a population size (number of individuals). Save and click on the tab to access the next interface (MICROBIOMES).

  6. Within MICROBIOMES, you can assign B-regions (bacterial lineages) to other regions of higher hierarchy (P-, RS- and H- membranes) in the P-system configuration. The whole population of simulated B-membranes within each P-, RS- and H- membrane constitute the intrinsic microbiome of these membranes. To do this, the first step is to type the number of lineages you want to compute and click on the “Add bacterial lineage” tab. Again as in other interfaces a summary table will appear, then specify name, cellular-gram and GEC (Genetic Exchange Community) status for each lineage. Two options (– and +) are available for gram status while you can define the GEC status with number labels (this is bacteria B1 and B2 belong to GEC 1, bacteria B3 and B4 belong to GEC 2, and so on). Then click on the “Create bacterial lineage types” tab to save the indications. Below you will see that the P-system configuration is now organized as a Venn diagram where the previously created P-, RS- and H- membranes are distinguished by colors. Finally, for each membrane you only need to click on “Assign” tab to invoke a new table where you can select the lineage types you want to assign to the selected container region as well as the number of cells you want per lineage. Additionally and for computational sake you have the option to select a magnitude to deal with this number according to a basal realistic computational unit to process at each iteration. The system accepts the following magnitudes:

    • Cell units (c): 1 cell
    • Kilocells (Kc): 103 cells
    • decaKilocells (dKc): 10·103 cells
    • hectoKilocells (hKc): 102·103 cells
    • Megacells (Mc): 106 cells
    • Gigacells (Gc): 109 cells
    • Teracells (Tc): 1012 cells

    Finally, you only need to save such a configuration and do the same for the next P-, RS- or H-membrane you want to assign a microbiome. When having all regions configured go to the next interface by clicking on the “OBJECTS” tab at the bottom of the interface.

  7. Within OBJECTS, you can specify plasmids, resistance genes, clocks and substances, and introduce them to the previously defined environments, reservoirs, hosts or microbiomes.

    For it, first click on the “Add/Edit objects” tab of any membrane. Then, choose the number of object types you want to create and next click on the “Add objects” tab. Next, you will type an ID and name for each type of object, as well as the number of objects of each category.

    The system only considers the following IDs (case sensitive, n is an integer number):

    • PLn: for plasmids.
    • ARn: for resistance genes.
    • PLn-ARn, PLn-ARn1-ARn2: for resistance genes in plasmids.
    • Gn: for clocks. Can only be assigned to reservoirs.

    You can check if everything is all right by looking at the Venn diagram, where a set of blue boxes within each region describing the object type and abundance will be displayed. If so, then click on the tab SPECIFICATIONS.

  8. Within SPECIFICATIONS you will be able to tune bacteria or host population density, life expectancy, half-life of antibiotics/biocides, host age, birth rate, maximum number of resistance genes per bacterial genome and maximum number of plasmids per bacterial cell.

    Proceed as follows:

    Click on the “Add/Edit Specifications” tab of any membrane, then the “Add specification” tab within that membrane. A list all available precompiled specifications is displayed. To select a particular specification, click on the “specification” tab in order to make it editable, then add the names of objects and regions to which you want to assign this particular specification, as well as the values and parameters that you consider appropriate. Then click on the “Save” tab to store the specification.

    The summary of specifications will be listed with the added values in blue. If you need more specifications (and there are more available) select, configure and save them (remember one-to-one) in the same way. If everything is done then go back to the Venn diagram. Note that each region shows a label (after the region name) specifying how many specifications have been assigned to the region. Then proceed to RULES (bottom tab).

  9. Now you are ready to burn the last stage: within RULES, you will setup parameters and values for interaction, movement and evolution of the distinct regions and objects.

    The procedure is as follows:

    By clicking on the “Add/Edit Rules” tab of any membrane, and next “Add rule”, a list of all available precompiled rules will be displayed. Select a set of rules for this particular region one by one, by clicking “Define rule” in order to make it editable, then add the names of objects and regions to which you want assign this rule, as well the appropiate values and parameters. Then click on the “Save” tab to store the rule.

    The summary of rules you have configured for each region and the added values will appear in blue in the Venn diagram. Now the system is configured.

Launch the simulation

  1. Click “RUN” tab and specify one of your stored configurations and the number of iterations (days) (2.000 maximum). Note that the simulation can take several hours.

  2. Check your OUTPUT files by clicking on the said tab: ECO-like.csv, P-like.csv, RS-like.csv, H-like.csv, B-like.csv. Each one of these files contains the counts of regions and objects per iteration and at a particular membrane level. You can download all at once as a single zip file or one by one.

Citing ARES:
Marcelino Campos, Carlos Llorens, José M. Sempere, Ricardo Futami, Irene Rodriguez, Purificación Carrasco, Rafael Capilla, Amparo Latorre, Teresa M. Coque, Andres Moya and Fernando Baquero. 2015. A membrane computing simulator of trans-hierarchical antibiotic resistance evolution dynamics in nested ecological compartments (ARES). Biology Direct 2015, 10:41.