Nutrient Transport Shapes Antibiotic Efficacy in Structured Bacterial Populations

As antibiotic resistance has emerged as a growing global health threat, there is an unmet need to enhance and prolong the usage of our current antibiotics. For single cells, the efficacy of many antibiotics is known to depend on cellular metabolism, and thus, the local abundance of nutrients. In large, multicellular, spatially structured populations (e.g. biofilms), cells themselves reshape their local chemical environment through consumption, leading to strong spatiotemporal variations in nutrient abundance. Indeed, it has long been hypothesized that chemical gradients within biofilms are partly responsible for their increased tolerance to antibiotic treatment. In this work, we develop an experimentally tractable system to investigate the synergistic effects of nutrient (glucose) and antibiotic (fosfomycin) gradients on structured bacterial (E. coli) populations in real-time with confocal microscopy. Our experimental results, combined with biophysical modeling, elucidate how localized nutrient gradients and antibiotic efficacy are actively shaped by the competition between nutrient transport processes as well as bacterial density, spatial distribution, metabolic state, and antibiotic sensitivity. Taken together, these results provide promising new avenues for improving treatment efficacy using current antibiotic therapies.

Funding from: NSF GRFP #DGE-2039656