Bacterial charity work leads to population-wide resistance

The emergence of antibiotic-resistant bacterial strains is a growing threat in clinical environments, but the process by which they arise is not well understood. Experiments using a continuous culture of Escherichia coli exposed to increasing concentrations of an antibiotic show that a few spontaneous drug-resistant mutants can protect the majority of the population. These highly resistant isolates produce the signalling molecule indole, which activates drug efflux pumps and other protective mechanisms in susceptible kin. This altruism allows weaker constituents to survive and to have the chance of beneficial mutation. More work on the use of intracellular communication by bacteria may prove of value for the rational design of clinical interventions to control resistant bacterial infections. Bacteria regularly evolve antibiotic resistance, but little is known about this process at the population level. Here, a continuous culture of Escherichia coli facing increasing antibiotic levels is followed. Most isolates taken from this population are less antibiotic resistant than the population as a whole. A few highly resistant mutants provide protection to the less resistant constituents, in part by producing the signalling molecule indole, which serves to turn on drug efflux pumps and oxidative-stress protective mechanisms. Bacteria show remarkable adaptability in the face of antibiotic therapeutics. Resistance alleles in drug target-specific sites and general stress responses have been identified in individual end-point isolates1,2,3,4,5,6,7. Less is known, however, about the population dynamics during the development of antibiotic-resistant strains. Here we follow a continuous culture of Escherichia coli facing increasing levels of antibiotic and show that the vast majority of isolates are less resistant than the population as a whole. We find that the few highly resistant mutants improve the survival of the population’s less resistant constituents, in part by producing indole, a signalling molecule generated by actively growing, unstressed cells8. We show, through transcriptional profiling, that indole serves to turn on drug efflux pumps and oxidative-stress protective mechanisms. The indole production comes at a fitness cost to the highly resistant isolates, and whole-genome sequencing reveals that this bacterial altruism is made possible by drug-resistance mutations unrelated to indole production. This work establishes a population-based resistance mechanism constituting a form of kin selection9 whereby a small number of resistant mutants can, at some cost to themselves, provide protection to other, more vulnerable, cells, enhancing the survival capacity of the overall population in stressful environments.