Adaption to glucose limitation is modulated by the pleotropic regulator CcpA, independent of selection pressure strength

Claire E. Price, Filipe Branco Dos Santos, Anne Hesseling, Jaakko J. Uusitalo, Herwig Bachmann, Vera Benavente, Anisha Goel, Jan Berkhout, Frank J. Bruggeman, Siewert Jan Marrink, Manolo Montalban-Lopez, Anne De Jong, Jan Kok, Douwe Molenaar, Bert Poolman, Bas Teusink*, Oscar P. Kuipers

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Background: A central theme in (micro)biology is understanding the molecular basis of fitness i.e. which strategies are successful under which conditions; how do organisms implement such strategies at the molecular level; and which constraints shape the trade-offs between alternative strategies. Highly standardized microbial laboratory evolution experiments are ideally suited to approach these questions. For example, prolonged chemostats provide a constant environment in which the growth rate can be set, and the adaptive process of the organism to such environment can be subsequently characterized. Results: We performed parallel laboratory evolution of Lactococcus lactis in chemostats varying the quantitative value of the selective pressure by imposing two different growth rates. A mutation in one specific amino acid residue of the global transcriptional regulator of carbon metabolism, CcpA, was selected in all of the evolution experiments performed. We subsequently showed that this mutation confers predictable fitness improvements at other glucose-limited growth rates as well. In silico protein structural analysis of wild type and evolved CcpA, as well as biochemical and phenotypic assays, provided the underpinning molecular mechanisms that resulted in the specific reprogramming favored in constant environments. Conclusion: This study provides a comprehensive understanding of a case of microbial evolution and hints at the wide dynamic range that a single fitness-enhancing mutation may display. It demonstrates how the modulation of a pleiotropic regulator can be used by cells to improve one trait while simultaneously work around other limiting constraints, by fine-tuning the expression of a wide range of cellular processes.

Original languageEnglish
Article number15
Pages (from-to)1-15
Number of pages15
JournalBMC Evolutionary Biology
Issue number1
Publication statusPublished - 10 Jan 2019


This study was funded by the Kluyver Centre for Genomics of Industrial Fermentation and the Netherlands Consortium for Systems Biology (NCSB), within the framework of the Netherlands Genomics Initiative (NGI)/NWO. FBS, FJB and BT are supported by the Netherlands Organization for Scientific Research (NWO) through VENI grant 863.11.019, VIDI grant 864.11.011 and VICI grant 865.14.005 respectively.

FundersFunder number
Kluyver Centre for Genomics of Industrial Fermentation
Netherlands Consortium for Systems Biology
Netherlands Organization for Scientific Research863.11.019, 864.11.011, 865.14.005
Nederlandse Organisatie voor Wetenschappelijk Onderzoek


    • Evolution
    • Lactic acid bacteria
    • Systems biology


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