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Center for Nonlinear Studies |
The recent rise in microbial drug resistance is a growing challenge for future therapy of bacterial infections. Conjugation is a key mechanism of horizontal gene transfer and the main culprit in the spread of bacterial antibiotic resistance. During conjugation, antibiotic resistance genes present on mobile plasmids are transferred from antibiotic resistant cells, known as donors, to antibiotic resistance-deficient recipient cells. Bacteria of the genus Enterococcus faecalis are especially antibiotic-resistant nosocomial pathogens. In this presentation, I will discuss the gene regulatory components controlling the transfer of the tetracycline resistance conferring plasmid pCF10 in bacterium E. faecalis between plasmid-carrying donor cells and plasmid-deficient recipient cells. Transfer of this plasmid is initiated by a dual-chemical signal based communication between donor and recipient cells. Conjugative transfer of the plasmid is tightly controlled by two-key genes prgQ and prgX present on plasmid pCF10 in response to a pheromone secreted by recipient cells. Using mathematical modeling and experimentation, a novel mechanism of gene-regulation via transcriptional interference and antisense RNA interaction in the prgX/prgQ operon would be described. This multi-layered gene-regulatory mechanism plays a pivotal role in conferring to the pCF10 based system a robust bistable genetic switch controlling conjugative gene transfer. Additionally, donor cells “intelligently” fine tune response to pheromone by changing the number of copies of the pCF10 plasmid inside the cell, with higher copies generating increased robustness of the bistable switch and lower sensitivity to pheromone. Lastly, the role of quorum sensing based communication between donor cells to coordinate response to induction by recipient cells will be discussed. Using both experimentation and mathematical modeling, mechanisms controlling turn-ON and turn-OFF conjugation for the pCF10 system are elucidated. These mechanisms are critical both for the transfer of plasmid and survival of the donor cell. This study provides understanding of the mechanism of antibiotic resistance transfer and identification of potential drug targets for blocking transmission of antibiotic resistance for use in future therapy.
Host: Alan Perelson, T-6