Synergy and antagonism in a genome-scale model of metabolic hijacking by bacteriophage

Bacteriophage auxiliary metabolic genes (AMGs) alter host metabolism by hijacking reactions. Previous studies used functional annotations to infer AMG impacts, but how these propagate and interact to affect global metabolism and phage production remains understudied. We demonstrate the first integration of AMGs and phage assembly into a genome-scale metabolic model, using P-HM2 infection of Prochloroccocus marinus MED4 as a test system. Our model predicts that 17 directly hijacked reactions substantially impact over 30% of the metabolism, including carbon fixation, photosynthesis, and nucleotide synthesis. These indirect impacts are synergistically and antagonistically coupled. We find that hijacked reactions are either phage-aligned–shifting feasible reaction velocities in accordance with maximal phage production–or phage-antialigned. Phage-alignment predicts changes to the host-phage biomass Pareto front: phage-aligned reactions limit host growth; phage-antialigned reactions do not. We provide a systems-level understanding of AMG perturbations, revealing nontrivial cascading effects and highlighting their role in shaping microbial functions.