Cross-feeding reshapes interactions between antibiotic stressors through metabolic feedbacks

Abstract

Stressors can combine to inhibit organismal growth or function more (synergy) or less (antagonism) strongly than expected from their individual effects, yet whether these interactions are intrinsic properties of cells or stressors, or emergent consequences of ecological interactions remains unclear. Antibiotic combinations provide a tractable model for studying stressor interactions, but have been characterized largely in bacterial monocultures. Here, we compared antibiotic stressor interactions in Escherichia coli growth in monoculture versus when cross-feeding with Salmonella enterica. Across 36 antibiotic pairs, cross-feeding frequently shifts interactions toward antagonism and away from synergy. In the sulfamethoxazole-trimethoprim pair, dual treatment increases carbon excretion by E. coli, promoting partner growth and attenuating stressor synergy through reciprocal metabolic feedback. Perturbing partner metabolite usage restores monoculture-like interaction outcomes across multiple drug pairs. Together, our results demonstrate that stressor interactions in microorganisms can emerge from ecological feedbacks mediated by metabolic excretion.