Mechanism of Antibiotic Resistant Transfer in Enterococcus faecalis in

Planktonic cells via competing sensing/antisensing system

Vu Tran, Che-Chi Shu, Gary Dunny, Wei-Shou Hu and Doraiswami Ramkrishna

The pathogen, Enterococcus faecalis, is a leading cause of hospital acquired infections1. Through conjugation, free-plasmid recipients receive a plasmid transferred from the donor cells, and subsequently become resistant to the antibiotic. In this process, two peptides, iCF10 and cCF10, regulate the generic circuit for conjugations2 and affect the response of both recipients and donors. iCF10 and cCF10 are produced from donors and recipients respectively, and play opposite roles for this plasmid transfer. With the presence of iCF10, the conjugation is being suppressed, whereas cCF10 will induce and promote the plasmid transfer. 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 low3.
We formulated a mathematical model that describes the dynamic interaction and responses of both recipient and donor populations with respect to cCF10/iCF10 ratio in a Planktonic environment. This model accounts for the following effects: 1/ molecular interaction, mechanistic genetic regulation of the conjugations, and 2/ population level, signal peptides and donor/recipient population. The mechanism was cross examined using mutants which were impaired cCF10 and/or iCF10. Two population balances are constructed for both donors and recipients. Probability of successful transferring event has also been incorporated in the model. We anticipate that the successful rate of plasmid transfer will vary with both populations and also depend on the probability distribution of successful transferring event. A higher donor concentration means a higher number of available plasmids to transfer but also lead to more production of iCF10, suppressing the conjugation to avoid any wasteful plasmid harboring. The similar competition also occurs with the recipients. This result will fully capture all different effects from both donors/recipients. Understanding the balancing act of the signaling system may shed light on new ways of controlling the spread of antibiotic resistance.

References:

1 Chatterjee, Anushree, Laura C. Cook, Che-Chi Shu, Doraiswami Ramkrishna, Gary M. Dunny and Wei- Shou Hu, â??Antagonistic self-sensing and mate-sensing signaling controls antibiotic-resistance transferâ? PNAS, 7086-7090, DOI: 10.1073/pnas.1212256110, Published April 2013.

2 Shu, Che-Chi, A. Chatterjee and Wei-Shou Hu, and Doraiswami Ramkrishna, â??Modeling of Gene Regulatory Processes by Population Mediated Signaling. New Applications of Population Balances,â? Chem. Eng. Sci., 70, 188-199, 2012.

3. Shu, Che-Chi, Doraiswami Ramkrishna, A Chatterjee and Wei-Shou Hu, "Bistability versus Bimodal Distributions in Gene Regulatory Processes from Population Balance Modeling," PLoS Computational Biology: el002140. doi:l0.1371/journal.pcbi.l002140, 7, August 2011.