Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression

Ryan Kerr, Sara Jabbari, Jessica Blair, Iain G Johnston

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Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown that significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalizable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show that differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Furthermore, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance.

Original languageEnglish
Article number20210771
Number of pages14
JournalJournal of The Royal Society Interface
Issue number186
Publication statusPublished - 26 Jan 2022

Bibliographical note

Funding Information:
R.K. thanks the Wellcome Trust for funding (grant reference 108876/Z/15/Z).

Publisher Copyright:
© 2022 The Authors.


  • Boolean modelling
  • acrAB
  • antimicrobial resistance
  • cell-to-cell variability
  • efflux pumps
  • heterogeneous pulsing

ASJC Scopus subject areas

  • Biotechnology
  • Biophysics
  • Bioengineering
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering


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