Skip to main content

Thank you for visiting nature.com. 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.

  • Letter
  • Published:

A competitive trade-off limits the selective advantage of increased antibiotic production

Nature Microbiology volume 1, Article number: 16175 (2016) Cite this article

Subjects

Abstract

In structured environments, antibiotic-producing microorganisms can gain a selective advantage by inhibiting nearby competing species1. However, despite their genetic potential2,3, natural isolates often make only small amounts of antibiotics, and laboratory evolution can lead to loss rather than enhancement of antibiotic production4. Here, we show that, due to competition with antibiotic-resistant cheater cells, increased levels of antibiotic production can actually decrease the selective advantage to producers. Competing fluorescently labelled Escherichia coli colicin producers with non-producing resistant and sensitive strains on solid media, we found that although producer colonies can greatly benefit from the inhibition of nearby sensitive colonies, this benefit is shared with resistant colonies growing in their vicinity. A simple model, which accounts for such local competitive and inhibitory interactions, suggests that the advantage of producers varies non-monotonically with the amount of production. Indeed, experimentally varying the amount of production shows a peak in selection for producers, reflecting a trade-off between benefit gained by inhibiting sensitive competitors and loss due to an increased contribution to resistant cheater colonies. These results help explain the low level of antibiotic production observed for natural species and can help direct laboratory evolution experiments selecting for increased or novel production of antibiotics.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Colicin producers inhibit sensitive competitors in their vicinity, promoting their own growth as well as that of nearby resistant, non-producing cheaters.
Figure 2: Producers have an advantage over resistant cheaters only at high densities of sensitive competitors and low densities of producers.
Figure 3: A simple model of competition and inhibition predicts that selection for antibiotic production is maximized at intermediate production levels.
Figure 4: The advantage of producers over cheaters is maximized at an intermediate level of antibiotic production.

Similar content being viewed by others

References

  1. Chao, L. & Levin, B. R. Structured habitats and the evolution of anticompetitor toxins in bacteria. Proc. Natl Acad. Sci. USA 78, 6324–6328 (1981).

    Article  CAS  Google Scholar 

  2. Bentley, S. D., Chater, K. F. & Cerdeno, A. M. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417, 141–147 (2002).

    Article  Google Scholar 

  3. Oliynyk, M. et al. Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nat. Biotechnol. 25, 447–453 (2007).

    Article  CAS  Google Scholar 

  4. Le Gac, M. & Doebeli, M. Environmental viscosity does not affect the evolution of cooperation during experimental evolution of colicigenic bacteria. Evolution 64, 522–533 (2010).

    Article  CAS  Google Scholar 

  5. Hibbing, M. E., Fuqua, C., Parsek, M. R. & Peterson, S. B. Bacterial competition: surviving and thriving in the microbial jungle. Nat. Rev. Microbiol. 8, 15–25 (2009).

    Article  Google Scholar 

  6. Clardy, J., Fischbach, M. A. & Currie, C. R. The natural history of antibiotics. Curr. Biol. 19, R437–R441 (2009).

    Article  CAS  Google Scholar 

  7. D'Costa, V. M., McGrann, K. M., Hughes, D. W. & Wright, G. D. Sampling the antibiotic resistome. Science 311, 374–377 (2006).

    Article  CAS  Google Scholar 

  8. Feldgarden, M. & Riley, M. A. High levels of colicin resistance in Escherichia coli. Evolution 52, 1270–1276 (1998).

    Article  CAS  Google Scholar 

  9. Chait, R., Vetsigian, K. & Kishony, R. What counters antibiotic resistance in nature? Nat. Chem. Biol. 8, 2–5 (2011).

    Article  Google Scholar 

  10. Chait, R., Palmer, A. C., Yelin, I. & Kishony, R. Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments. Nat. Commun. 7, 10333 (2016).

    Article  CAS  Google Scholar 

  11. Butler, M. J. et al. Engineering of primary carbon metabolism for improved antibiotic production in Streptomyces lividans. Appl. Environ. Microbiol. 68, 4731–4739 (2002).

    Article  CAS  Google Scholar 

  12. Reeves, A. R., Cernota, W. H., Brikun, I. A. & Wesley, R. K. Engineering precursor flow for increased erythromycin production in Aeromicrobium erythreum. Metab. Eng. 6, 300–312 (2004).

    Article  CAS  Google Scholar 

  13. Andersson, D. I. & Hughes, D. Microbiological effects of sublethal levels of antibiotics. Nat. Rev. Microbiol. 12, 465–478 (2014).

    Article  CAS  Google Scholar 

  14. Linares, J. F., Gustafsson, I., Baquero, F. & Martinez, J.L. Antibiotics as intermicrobial signaling agents instead of weapons. Proc. Natl Acad. Sci. USA 103, 19484–19489 (2006).

    Article  CAS  Google Scholar 

  15. Lopez, D., Fischbach, M. A., Chu, F., Losick, R. & Kolter, R. Structurally diverse natural products that cause potassium leakage trigger multicellularity in Bacillus subtilis. Proc. Natl Acad. Sci. USA 106, 280–285 (2009).

    Article  CAS  Google Scholar 

  16. Wang, Y., Kern, S. E. & Newman, D. K. Endogenous phenazine antibiotics promote anaerobic survival of Pseudomonas aeruginosa via extracellular electron transfer. J. Bacteriol. 192, 365–369 (2010).

    Article  CAS  Google Scholar 

  17. Goh, E.-B. et al. Transcriptional modulation of bacterial gene expression by subinhibitory concentrations of antibiotics. Proc. Natl Acad. Sci. USA 99, 17025–17030 (2002).

    Article  CAS  Google Scholar 

  18. Adams, J., Kinney, T., Thompson, S. & Rubin, L. Frequency-dependent selection for plasmid-containing cells of Escherichia coli. Genetics 91, 627–637 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gore, J., Youk, H. & van Oudenaarden, A. Snowdrift game dynamics and facultative cheating in yeast. Nature 459, 253–256 (2009).

    Article  CAS  Google Scholar 

  20. Yurtsev, E. A., Chao, H. X., Datta, M. S., Artemova, T. & Gore, J. Bacterial cheating drives the population dynamics of cooperative antibiotic resistance plasmids. Mol. Syst. Biol. 9, 683 (2013).

    Article  CAS  Google Scholar 

  21. Diggle, S. P., Griffin, A. S., Campbell, G. S. & West, S. A. Cooperation and conflict in quorum-sensing bacterial populations. Nature 450, 411–414 (2007).

    Article  CAS  Google Scholar 

  22. Keller, L. & Surette, M. G. Communication in bacteria: an ecological and evolutionary perspective. Nat. Rev. Microbiol. 4, 249–258 (2006).

    Article  CAS  Google Scholar 

  23. Kerr, B., Riley, M. A., Feldman, M. W. & Bohannan, B. Local dispersal promotes biodiversity in a real-life game of rock–paper–scissors. Nature 418, 171–174 (2002).

    Article  CAS  Google Scholar 

  24. Kelsic, E. D., Zhao, J., Vetsigian, K. & Kishony, R. Counteraction of antibiotic production and degradation stabilizes microbial communities. Nature 521, 516–519 (2015).

    Article  CAS  Google Scholar 

  25. Wintermute, E. H. & Silver, P. A. Emergent cooperation in microbial metabolism. Mol. Syst. Biol. 6, 407 (2010).

    Article  Google Scholar 

  26. Kirkup, B. C. & Riley, M. A. Antibiotic-mediated antagonism leads to a bacterial game of rock–paper–scissors in vivo. Nature 428, 412–414 (2004).

    Article  CAS  Google Scholar 

  27. Charusanti, P. et al. Exploiting adaptive laboratory evolution of Streptomyces clavuligerus for antibiotic discovery and overproduction. PLoS ONE 7, e33727 (2012).

    Article  CAS  Google Scholar 

  28. Riley, M. A. & Wertz, J. E. Bacteriocin diversity: ecological and evolutionary perspectives. Biochimie 84, 357–364 (2002).

    Article  CAS  Google Scholar 

  29. Schaller, K. & Nomura, M. Colicin E2 is DNA endonuclease. Proc. Natl Acad. Sci. USA 73, 3989–3993 (1976).

    Article  CAS  Google Scholar 

  30. Cole, S. T. & Saint, B. Molecular characterisation of the colicin E2 operon and identification of its products. Mol. Gen. Genet. 198, 465–472 (1985).

    Article  CAS  Google Scholar 

  31. Weber, M. F., Poxleitner, G., Hebisch, E., Frey, E. & Opitz, M. Chemical warfare and survival strategies in bacterial range expansions. J. R. Soc. Interface 11, 20140172 (2014).

    Article  Google Scholar 

  32. Olano, C., Lombó, F., Méndez, C. & Salas, J. A. Improving production of bioactive secondary metabolites in actinomycetes by metabolic engineering. Metab. Eng. 10, 281–292 (2008).

    Article  CAS  Google Scholar 

  33. Russell, A. B., Peterson, S. B. & Mougous, J. D. Type VI secretion system effectors: poisons with a purpose. Nat. Rev. Microbiol. 12, 137–148 (2014).

    Article  CAS  Google Scholar 

  34. Maurer, R., Meyer, B. J. & Ptashne, M. Gene regulation at the right operator (OR) of bacteriophage λ. J. Mol. Biol. 139, 147–161 (1980).

    Article  CAS  Google Scholar 

  35. Lutz, R. & Bujard, H. Independent and tight regulation of transcriptional units in Escherichia coli via the LacR/O, the TetR/O and AraC/I1-I2 regulatory elements. Nucleic Acids Res. 25, 1203–1210 (1997).

    Article  CAS  Google Scholar 

  36. Chait, R., Shrestha, S., Shah, A. K., Michel, J.-B. & Kishony, R. A differential drug screen for compounds that select against antibiotic resistance. PLoS ONE 5, e15179 (2010).

    Article  Google Scholar 

  37. Coffin, D. DCRAW: decoding raw digital photos in Linux (2008); http://www.cybercom.net/~dcoffin/dcraw/

Download references

Acknowledgements

The authors thank E. Kelsic, A. Palmer and M. Elowitz for comments on the manuscript and E. Toprak for providing the colicin strains. Y.G. acknowledges support from the Hertz Foundation and the National Science Foundation (NSF) Graduate Research Fellowship. M.K. acknowledges support from NSF grant no. 1349248. R.K. acknowledges the support of the European Research Council Seventh Framework Programme (ERC grant no. 281891), the National Institutes of Health (grant no. R01GM081617) and the Israeli Centers of Research Excellence I-CORE Program (ISF grant no. 152/11).

Author information

Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Ylaine Gerardin & Michael Springer

  2. Faculty of Biology and Faculty of Computer Science, Technion – Israel Institute of Technology, 3200003, Haifa, Israel

    Roy Kishony

Authors
  1. Ylaine Gerardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roy Kishony
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.G., M.S. and R.K. designed the study. Y.G. performed experiments and analysis. Y.G., M.S. and R.K. interpreted the results and wrote the manuscript.

Corresponding authors

Correspondence to Michael Springer or Roy Kishony.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Figures 1–12, Supplementary Table 1 (PDF 1675 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gerardin, Y., Springer, M. & Kishony, R. A competitive trade-off limits the selective advantage of increased antibiotic production. Nat Microbiol 1, 16175 (2016). https://doi.org/10.1038/nmicrobiol.2016.175

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/nmicrobiol.2016.175

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

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