A nutrient bottleneck limits antibiotic efficacy in structured bacterial populations

Antibiotic resistance is a growing global health threat. Therefore, it is critically important to optimize how existing antibiotics act against bacterial infections. Although antibiotic activity is well studied at the single cell level, many infections are caused by spatially structured multicellular populations. In such populations, cellular consumption of scarce nutrients establishes strong spatial variations in their abundance. These nutrient variations have long been hypothesized to help bacterial populations tolerate antibiotics, since single-cell studies show that antibiotic tolerance depends on metabolic activity, and thus, local nutrient availability. Here, we directly test this hypothesis by visualizing cell death in Escherichia coli populations with defined structures upon exposure to nutrient (glucose) and antibiotic (fosfomycin). We find that nutrient availability acts as a bottleneck to antibiotic killing, causing death to propagate through the population as a traveling front—a phenomenon predicted over 20 years ago, but never verified until now. By integrating our measurements with biophysical theory and simulations, we establish quantitative principles that explain how collective nutrient consumption can limit the progression of this “death front,” protecting a population from a nominally deadly antibiotic dose. While increasing nutrient supply can overcome this bottleneck, our work reveals that in some cases, excess nutrient can unexpectedly promote the regrowth of resistant cells. Altogether, this work provides a key step toward predicting and controlling antibiotic treatment of spatially structured bacterial populations, yielding fundamental biophysical insights into collective behavior and helping to guide strategies for more effective antibiotic stewardship.