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

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

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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.

Natural microbial isolates, in particular those from soil environments, are known for their potential ability to synthesize a range of antibiotics5,6. In these dense ecosystems, where antibiotic producers and resistant and sensitive species coexist7–10, the ability to inhibit nearby species can give a producer a competitive advantage. Often, however, natural producers are not maximizing their production potential: metabolic engineering of natural species can increase the production of antibiotics several-fold without a significant reduction in growth11,12. It is possible that high production levels are still costly in nature, or that antibiotics are produced in small amounts not for inhibition of competitors, but because they instead function as signalling molecules at sub-inhibitory concentrations13–17. Alternatively, it is possible that the low production level of antibiotics stems directly from their inhibitory role: in complex ecosystems, high toxicity against competitors, even at no cost, may not be the most advantageous strategy. It remains unclear whether there are indeed inherent limits on the optimal level of antibiotic production when focusing only on their toxic activity against competing species.

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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.

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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).

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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

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  1. Ylaine Gerardin
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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.

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Correspondence to Michael Springer or Roy Kishony.

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

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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

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