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Bacterial charity work leads to population-wide resistance

Abstract

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.

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Figure 1: Tracking a population of E. coli developing antibiotic resistance.
Figure 2: Indole production by isolates and the protective effect of extracellular indole.
Figure 3: Whole-genome sequencing of various mutants.
Figure 4: A population-based antibiotic-resistance mechanism.

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Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the NCBI Gene Expression Omnibus under GEO Series accession number GSE22833.

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Acknowledgements

We thank M. Chaparian and Q. Beg for help with bioreactor instrumentation. We also thank A. Herbert and C. Ordija for use of the Covaris sonicator for preparing sequencing libraries. This work was supported by the National Institutes of Health through the NIH Director’s Pioneer Award Program, grant number DP1OD003644; the National Science Foundation through RTG grant number DMS-0602204; and the Howard Hughes Medical Institute.

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All authors designed the study. H.H.L. and M.N.M. performed and analysed the experiments with input from C.R.C. and J.J.C. All authors prepared and commented on the manuscript.

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Correspondence to James J. Collins.

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The authors declare no competing financial interests.

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Lee, H., Molla, M., Cantor, C. et al. Bacterial charity work leads to population-wide resistance. Nature 467, 82–85 (2010). https://doi.org/10.1038/nature09354

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