Weakest link dynamics predict apparent antibiotic interactions in a model cross-feeding community.

Abstract

With the growing global threat of antimicrobial resistance, novel strategies are required for combatting resistant pathogens. Combination therapy, wherein multiple drugs are used to treat an infection, has proven highly successful in the treatment of cancer and HIV. However, this practice has proven challenging for the treatment of bacterial infections due to difficulties in selecting the correct combinations and dosages. An additional challenge in infection treatment is the polymicrobial nature of many infections, which may respond to antibiotics differently than a monoculture pathogen. This study tests whether patterns of antibiotic interactions (synergy, antagonism, or independence/additivity) in monoculture can be used to predict antibiotic interactions in an obligate cross-feeding co-culture. Using our previously described weakest link hypothesis, we hypothesized antibiotic interactions in co-culture based on the interactions we observed in monoculture. We then compared our predictions to observed antibiotic interactions in co-culture. We tested the interactions between ten previously identified antibiotic combinations using checkerboard assays. Although our antibiotic combinations interacted differently than predicted in our monocultures, our monoculture results were generally sufficient to predict co-culture patterns based solely on the weakest link hypothesis. These results suggest that combination therapy for cross-feeding multispecies infections may be successfully designed based on antibiotic interaction patterns for their component species.