Extent and control of plasmid conjugation: dynamics, interactions and barriers

Abstract

Plasmid conjugation is the preferred route of dissemination of important adaptive traits in bacteria, such as antibiotic resistance genes. If conjugation could be tamed and controlled at will, we will have a strong hand to control antibiotic resistance acquisition by human pathogens. To achieve this objective, we determined the dynamics of plasmid conjugation using various plasmid prototypes. We could distinguish between density-dependent and frequency-dependent conjugation dynamics. Broad-host range plasmids, which show inherently high conjugation rates (R0 >1), are able to invade recipient populations. This is in contrast to repressed plasmids, such as members of the MOBF12 / IncF complex, which show R0 <1. Comparative genomics analysis shows that the transfer systems of MOBF12 / IncF are adapted to their host bacteria and show interesting variations in their regulatory systems. Besides, and using plasmid R388 as a model, we determined how interactions with other plasmids and host chromosomes greatly affect the plasmid rate of transfer. Additionally, we screened a large series of compounds as conjugation inhibitors and investigated the mechanisms by which they affect conjugation. These inhibitors are able to eliminate plasmid invasion of recipient populations. Finally, we developed a genome analysis tool, called PLACNET, which helps in reconstructing plasmids from whole genome sequences. PLACNET has now been updated as a web tool that can be run from a PC. Using PLACNET, we were able to show that E. coli ST131, sometimes considered as an E. coli clone, contains nearly as much plasmid diversity as the whole enterobacteria. All these results taken together suggest new approaches to control plasmid conjugation and, thus, the dissemination of antibiotic resistance to human pathogens.