Cocktail combinations of bacteria-infecting viruses (bacteriophages) can suppress pathogenic bacterial growth. However, predicting how phage cocktails influence microbial communities with complex ecological interactions, specifically cross-feeding interactions in which bacteria exchange nutrients, remains challenging. Here, we used experiments and mathematical simulations to determine how to best suppress a model pathogen, E. coli, when obligately cross-feeding with S. enterica. We tested whether the duration of pathogen suppression caused by a two-lytic phage cocktail was maximized when both phages targeted E. coli, or when one phage targeted E. coli and the other its cross-feeding partner, S. enterica. Experimentally, we observed that cocktails targeting both cross-feeders suppressed E. coli growth longer than cocktails targeting only E. coli. Two non-mutually exclusive mechanisms could explain these results: (i) we found that treatment with two E. coli phage led to the evolution of a mucoid phenotype that provided cross-resistance against both phages, and (ii) S. enterica set the growth rate of the coculture, and therefore, targeting S. enterica had a stronger effect on pathogen suppression. Simulations suggested that cross-resistance and the relative growth rates of cross-feeders modulated the duration of E. coli suppression. More broadly, we describe a novel bacteriophage cocktail strategy for pathogens that cross-feed.
Bibliographical noteFunding Information:
L. Fazzino was supported by a Fellowship from the Institute for Molecular Virology Training Program (NIH T32 AI083196). Research was also supported through the NIH (GM121498-01A1, to William Harcombe). We would like to thank Sarah P. Hammarlund, Harcombe Lab members and the UMN Institute for Molecular Virology community for useful discussions, and two anonymous reviewers for their comments. L. Fazzino was supported by a Fellowship from the Institute for Molecular Virology Training Program (NIH T32 AI083196). Research was also supported through the NIH (GM121498-01A1, to William Harcombe).