Modeling the Directed Evolution of Broad Host Range Phages

Background: The host ranges of individual phages tend to be narrow, yet many applications of phages would benefit from expanded host ranges. Empirical methods have been developed to direct the evolution of phages to attack new strains, but the methods have not been evaluated or compared for their consequences. In particular, how do different methods favor generalist (broad host range) phages over specialist phages? All methods involve exposing phages to two or more novel bacterial strains, but the methods differ in the order in which those hosts are presented through time: Parallel presentation, Sequential presentation, and Mixed presentation. Methods: We use a combination of simple analytical methods and numerical analyses to study the effect of these different protocols on the selection of generalist versus specialist phages. Results: The three presentation protocols have profoundly different consequences for the evolution of generalist versus specialist phages. Sequential presentation favors generalists almost to the exclusion of specialists, whereas Parallel presentation does the least so. However, other protocol attributes (the nature of dilution between transfers of phages to new cultures) also have effects on selection and phage maintenance. It is also noted that protocols can be designed to enhance recombination to augment evolution and to reduce stochastic loss of newly arisen mutants.