Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Bacterial charity work leads to population-wide resistance


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes

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.


  1. Albert, T. J. et al. Mutation discovery in bacterial genomes: metronidazole resistance in Helicobacter pylori . Nature Methods 2, 951–953 (2005)

    Article  CAS  Google Scholar 

  2. Smith, B. T. & Walker, G. C. Mutagenesis and more: umuDC and the Escherichia coli SOS response. Genetics 148, 1599–1610 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bjedov, I. et al. Stress-induced mutagenesis in bacteria. Science 300, 1404–1409 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Miller, J. H. Spontaneous mutators in bacteria: insights into pathways of mutagenesis and repair. Annu. Rev. Microbiol. 50, 625–643 (1996)

    Article  CAS  Google Scholar 

  5. Friedman, L., Alder, J. D. & Silverman, J. A. Genetic changes that correlate with reduced susceptibility to daptomycin in Staphylococcus aureus. Antimicrob. Agents Chemother. 50, 2137–2145 (2006)

    Article  CAS  Google Scholar 

  6. Kohanski, M. A., DePristo, M. A. & Collins, J. J. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol. Cell 37, 311–320 (2010)

    Article  CAS  Google Scholar 

  7. Wang, H., Dzink-Fox, J. L., Chen, M. & Levy, S. B. Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrR mutations. Antimicrob. Agents Chemother. 45, 1515–1521 (2001)

    Article  CAS  Google Scholar 

  8. Gooder, H. & Happold, F. C. The tryptophanase-tryptophan reaction; the nature of the enzyme-coenzyme-substrate complex. Biochem. J. 57, 369–374 (1954)

    Article  CAS  Google Scholar 

  9. West, S. A., Griffin, A. S., Gardner, A. & Diggle, S. P. Social evolution theory for microorganisms. Nature Rev. Microbiol. 4, 597–607 (2006)

    Article  CAS  Google Scholar 

  10. Woodford, N. & Ellington, M. J. The emergence of antibiotic resistance by mutation. Clin. Microbiol. Infect. 13, 5–18 (2007)

    Article  CAS  Google Scholar 

  11. Livermore, D. M. Bacterial resistance: origins, epidemiology, and impact. Clin. Infect. Dis. 36 (suppl. 1). S11–S23 (2003)

    Article  CAS  Google Scholar 

  12. Smith, P. A. & Romesberg, F. E. Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation. Nature Chem. Biol. 3, 549–556 (2007)

    Article  CAS  Google Scholar 

  13. Hirakawa, H., Inazumi, Y., Masaki, T., Hirata, T. & Yamaguchi, A. Indole induces the expression of multidrug exporter genes in Escherichia coli . Mol. Microbiol. 55, 1113–1126 (2005)

    Article  CAS  Google Scholar 

  14. Kobayashi, A., Hirakawa, H., Hirata, T., Nishino, K. & Yamaguchi, A. Growth phase-dependent expression of drug exporters in Escherichia coli and its contribution to drug tolerance. J. Bacteriol. 188, 5693–5703 (2006)

    Article  CAS  Google Scholar 

  15. Lee, J. H. & Lee, J. Indole as an intercellular signal in microbial communities. FEMS Microbiol. Rev. 34, 426–444 (2010)

    Article  CAS  Google Scholar 

  16. Travisano, M. & Lenski, R. E. Long-term experimental evolution in Escherichia coli. IV. Targets of selection and the specificity of adaptation. Genetics 143, 15–26 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Altuvia, S., Weinstein-Fischer, D., Zhang, A., Postow, L. & Storz, G. A small, stable RNA induced by oxidative stress: role as a pleiotropic regulator and antimutator. Cell 90, 43–53 (1997)

    Article  CAS  Google Scholar 

  18. Dwyer, D. J., Kohanski, M. A., Hayete, B. & Collins, J. J. Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli . Mol. Syst. Biol. 3, 91 (2007)

    Article  Google Scholar 

  19. Kohanski, M. A., Dwyer, D. J., Hayete, B., Lawrence, C. A. & Collins, J. J. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130, 797–810 (2007)

    Article  CAS  Google Scholar 

  20. Kohanski, M. A., Dwyer, D. J., Wierzbowski, J., Cottarel, G. & Collins, J. J. Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death. Cell 135, 679–690 (2008)

    Article  CAS  Google Scholar 

  21. Tucker, N. P., Le Brun, N. E., Dixon, R. & Hutchings, M. I. There’s NO stopping NsrR, a global regulator of the bacterial NO stress response. Trends Microbiol 18, 149–156 (2010)

    Article  CAS  Google Scholar 

  22. Mouneimné, H., Robert, J., Jarlier, V. & Cambau, E. Type II topoisomerase mutations in ciprofloxacin-resistant strains of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 43, 62–66 (1999)

    Article  Google Scholar 

  23. Miller, P. F., Gambino, L. F., Sulavik, M. C. & Gracheck, S. J. Genetic relationship between soxRS and mar loci in promoting multiple antibiotic resistance in Escherichia coli . Antimicrob. Agents Chemother. 38, 1773–1779 (1994)

    Article  CAS  Google Scholar 

  24. Long, F., Rouquette-Loughlin, C., Shafer, W. M. & Yu, E. W. Functional cloning and characterization of the multidrug efflux pumps NorM from Neisseria gonorrhoeae and YdhE from Escherichia coli . Antimicrob. Agents Chemother. 52, 3052–3060 (2008)

    Article  CAS  Google Scholar 

  25. Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006.0008 (2006)

    Article  Google Scholar 

  26. Steiling, K. et al. Comparison of proteomic and transcriptomic profiles in the bronchial airway epithelium of current and never smokers. PLoS ONE 4, e5043 (2009)

    Article  ADS  Google Scholar 

  27. Lee, J., Jayaraman, A. & Wood, T. K. Indole is an inter-species biofilm signal mediated by SdiA. BMC Microbiol. 7, 42 (2007)

    Article  Google Scholar 

  28. Talloen, W. et al. I/NI-calls for the exclusion of non-informative genes: a highly effective filtering tool for microarray data. Bioinformatics 23, 2897–2902 (2007)

    Article  CAS  Google Scholar 

  29. Bentley, D. R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008)

    Article  ADS  CAS  Google Scholar 

  30. Herring, C. D. et al. Comparative genome sequencing of Escherichia coli allows observation of bacterial evolution on a laboratory timescale. Nature Genet. 38, 1406–1412 (2006)

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to James J. Collins.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figure 1 with legend, Supplementary Methods and Supplementary Table 1. (PDF 285 kb)

Supplementary Tables

This file contains Supplementary Table 2 (XLS 657 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee, H., Molla, M., Cantor, C. et al. Bacterial charity work leads to population-wide resistance. Nature 467, 82–85 (2010).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing