Abstract

It is often stated that slow-growing bacteria are more resistant to antibiotics, but so far there has been no mechanistic explanation for this claim. We have investigated systematically how the growth state of Escherichia coli bacteria affects their susceptibility to ribosome-targeting antibiotics. We find that the situation is more complex than usually assumed: while some antibiotics work better for fast-growing cells, others work better for slow-growing cells. It turns out that these observations can be explained by a simple mathematical model that combines drug transport and binding with physiological constraints. Our model reveals that growth-dependent susceptibility is controlled by a single parameter characterizing the `reversibility’ of antibiotic transport and binding. This parameter could provide an alternative to traditional ways of classifying antibiotics. Our result suggest potential strategies for differential targeting of chronic and acute infections, and could be extended to other classes of antibiotics.