The Cost and Benefit of Horizontal Gene Transfer

Plasmids are key vehicles of horizontal gene transfer (HGT), mobilizing antibiotic resistance, virulence, and other traits among bacterial populations. Their fitness is directed by two orthogonal processes—vertical transfer through cell division and horizontal transfer through conjugation. When considered individually, improvements in either mode of transfer can promote how well a plasmid spreads and persists. Together, however, the metabolic burden of conjugation could create a tradeoff between the two and constrain plasmid evolution. Furthermore, the environmental and genetic forces that drive plasmid transfer are poorly understood, due to the lack of definitive quantification coupled with genomic analysis. Knowing how conjugation influences plasmid fitness and, subsequently, how to influence conjugation opens the door for evolutionary therapies targeting antibiotic resistance and bacteria in general.

Here, we integrate conjugative phenotype with plasmid genotype to provide quantitative analysis of HGT in clinical Escherichia coli pathogens. We find a substantial proportion of these pathogens (>25%) able to readily spread resistance to the most common classes of antibiotics. Antibiotics of varied modes of action had less than a 5-fold effect on conjugation efficiency in general, with one exception displaying 31-fold promotion upon exposure to macrolides and chloramphenicol. In contrast, genome sequencing reveals plasmid incompatibility group strongly correlates with transfer efficiency. These findings offer new insights into the determinants of plasmid mobility and have implications for the development of treatments that target HGT.

We also present evidence for the presence, consequences, and molecular basis of a conjugation-burden tradeoff among 40 plasmids derived from clinical E. coli pathogens. We discover that most plasmids avoid a fitness tradeoff by operating below a conjugation efficiency threshold for burden, indicating strong selection for vertical transfer. In this region, E. coli demonstrates a remarkable growth tolerance to over four orders of magnitude change in conjugation efficiency. This tolerance fades as nutrients become scarce and horizontal transfer attracts a larger share of host resources. These results provide insight into evolutionary constraints directing plasmid fitness and strategies to combat the spread of antibiotic resistance.