(398d) Modeling for Complex Interactive Behaviors Among Enterococcus Faecalis Donor and Recipients in Biofilms

Authors: 
Tran, V., Purdue University
Bandyopadhyaya, A., University of Minnesota
Dunny, G. M., University of Minnesota
Ramkrishna, D., Purdue University
Hu, W. S., University of Minnesota, Twin Cities
The pathogen, Enterococcus faecalis, is a leading cause of hospital acquired infections. This species utilizes the mechanism of conjugation to transfer antibiotic resistance from plasmid-harboring antibiotic-resistant donors to plasmid-free antibiotic-sensitive recipients. Specifically, the plasmid pCF10 carried in the donors provides cells with the ability to resist to antibiotics. The two types of signaling molecules which regulate the conjugative transfer of this plasmid are inducer cCF10 and inhibitor iCF10. Peptide cCF10 is produced by recipients. In the presence of both cCF10 and donors in the environment, the peptides enter donor cells, leading to an induction of conjugation. Inhibitor iCF10, on the other hand, is produced by donors and functions to suppress the conjugation. Both types of signaling molecules, which are produced by cells to the environment, can then transfer to the donor cells. Depending on the domination of either cCF10 or iCF10, donors will have different responses: promoting the conjugation when the recipient cells are abundant and restraining the process when the recipient concentration is low.

We have formulated a mathematical stochastic model that captures the dynamic interaction and responses of both recipients and donors in the entire population. Both types of cells were embedded inside the biofilm and were influenced by both extracellular cCF10 and iCF10. The model also attempts to capture the plasmid spreading effect through which some recipients are converted into new donors. The biofilm is formulated as a 2D model and is composed of both donors and recipients. This model accounts for the following effects: 1) molecular interaction between intracellular quantities prior to conjugation, 2) mechanistic genetic regulation of the conjugations and the corresponding outcomes, and 3) population level, signal peptides and donor/recipient population in the biofilm and recipients. We anticipate that the initial locations of donors and recipients and the availability of signaling molecules within the biofilm can affect the plasmid transfer between cells. A higher donor concentration means a higher number of available plasmids to transfer but also leads to more production of iCF10, suppressing the conjugation to avoid any wasteful plasmid transfer. This model helps to evaluate these competitive effects in different scenarios and thus provides a full set of conditions at which some factors can be more dominant than others and has the potential to fully capture all the different effects from both donors and recipients. Understanding the balancing between different signaling mechanisms in this system may shed light on new ways of controlling the spread of antibiotic resistance.