Ratiometric quorum sensing in Enterococcus faecalis conjugation

Plasmid-mediated horizontal gene transfer of antibiotic-resistance and virulence in pathogenic bacteria underlies a major public health issue. Understanding how, in the absence of antibiotic-mediated selection, plasmid-bearing cells avoid being outnumbered by plasmid-free cells, is key to developing counter strategies. Here we quantified the induction of Enterococcus faecalis plasmidial sex-pheromone pathway to show that the integration of the stimulatory (mate-sensing) and inhibitory (self-sensing) signaling modules from the pCF10 conjugative plasmid, provides a precise measure of the recipient-to-donor ratio, agnostic to variations in population size. Such ratiometric control of conjugation favors vertical plasmid-transfer under low mating likelihood and allows activation of conjugation functions only under high mating likelihood. We further show that this strategy constitutes a cost-effective investment into mating effort, as overstimulation produces unproductive self-aggregation and reductions in the growth rate. A mathematical model suggests that ratiometric control of conjugation limits the spread of antibiotic resistance in absence of antibiotics, predicting a long-term stable co-existence of donors and recipients. Our results demonstrate how population-level parameters can control transfer of antibiotic-resistance in bacteria, opening the door for biotic control strategies. Ratiometric sensing in bacteria mirrors sexual behaviors observed in eukaryotes.