Title: Trade-offs and Trade-ups in Bacteria-Phage Coevolution

Abstract: Evolutionary trade-offs are thought to be a fundamental factor constraining adaptation in natural populations. Trade-offs have also been leveraged in the treatment of bacterial infections through selection by phage at the expense of antibiotic resistance. However, it is currently unknown how widespread and reliable such trade-offs may be. My group is using a combination of experimental evolution and molecular genetics to uncover when such tradeoffs may be in effect. We have discovered the potential for trade-offs between phage resistance and antibiotic resistance mediated by the lytic Escherichia coli phage U136B. We found that phage U136B adsorbs to TolC, which is an outer membrane protein component of a multidrug efflux pump. Using experimental evolution, we show that loss or modification of the tolC gene is a common evolutionary response to selection by phage U136B, whereby some phage resistant mutants have reduced antibiotic resistance. However, we also found that this trade-off strongly depended on the antibiotic, type of selection experiment, and the specific host resistance mutation. In some cases, bacteria even evaded the trade-off such that phage-resistant mutants had the same or greater antibiotic resistance. In new work, we are investigating alternative mutational pathways to phage resistance and the impact of host resistance on phage coevolution. Overall, our results suggest that phage resistance may sometimes, but not always, help maintain antibiotic sensitivity in bacterial populations.