UC San Diego

The number of multidrug resistant strains of bacteria is increasing rapidly, while the discovery of new antibiotics has stagnated. Subsequently, interest in bacteriophages as anti-bacterial therapeutics has surged, in part, because there is near limitless diversity of phages to harness. While this diversity provides opportunity, it also creates the dilemma of having to decide which criteria to use to select phages. Two traits previously proposed are thermostability and reproductive rate. Here we show that focusing on phage’s current abilities may be shortsighted if maximizing traits like stability and reproduction limits future evolution. We studied the ability of three phages to suppress bacteria. Each phage differed by only one amino acid at site 987 in their host-recognition protein (J), yet they varied significantly in their stability, growth rate, and evolvability. We uncovered a three-way tradeoff such that each phage maximized only two of the three traits. The most suppressive phage was an evolvable, fast-reproducing variant, supporting the importance of evolvability and reproduction rate. We tested whether these traits were interdependent but found that each had individual effects on suppression. Seeking to test the environmental contingency of our results, we altered the experiment to reflect more challenging conditions inside a patient’s body. The stable, fast-reproducing phage was most suppressive in the short term, but the fast-reproducing, evolvable phage was more suppressive in the long term. Our results highlight the importance of evolvability, an often-overlooked trait in phage therapy, and underscore the need to consider long-term dynamics when testing phage for therapeutic use.