From modules to networks: A systems-­level analysis of the bacitracin stress response in Bacillus subtilis

Hannah Piepenbreier, Andre Sim, Carolin M Kobras, Jara Radeck, Thorsten Mascher, Susanne Gebhard, Georg Fritz

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Abstract

Bacterial resistance against antibiotics often involves multiple mechanisms that are interconnected to ensure robust protection. So far, the knowledge about underlying regulatory features of those resistance networks is sparse, since they can hardly be determined by experimentation alone. Here, we present the first computational approach to elucidate the interplay between multiple resistance modules against a single antibiotic and how regulatory network structure allows the cell to respond to and compensate for perturbations of resistance. Based on the response of Bacillus subtilis toward the cell wall synthesis-inhibiting antibiotic bacitracin, we developed a mathematical model that comprehensively describes the protective effect of two well-studied resistance modules (BceAB and BcrC) on the progression of the lipid II cycle. By integrating experimental measurements of expression levels, the model accurately predicts the efficacy of bacitracin against the B. subtilis wild type as well as mutant strains lacking one or both of the resistance modules. Our study reveals that bacitracin-induced changes in the properties of the lipid II cycle itself control the interplay between the two resistance modules. In particular, variations in the concentrations of UPP, the lipid II cycle intermediate that is targeted by bacitracin, connect the effect of the BceAB transporter and the homeostatic response via BcrC to an overall resistance response. We propose that monitoring changes in pathway properties caused by a stressor allows the cell to fine-tune deployment of multiple resistance systems and may serve as a cost-beneficial strategy to control the overall response toward this stressor.
Original languageEnglish
Article numbere00687-19
JournalmSystems
Volume5
Issue number1
Early online date4 Feb 2020
DOIs
Publication statusE-pub ahead of print - 4 Feb 2020

Keywords

  • Antibiotic resistance
  • Antimicrobial peptide
  • Bacitracin
  • Cell wall antibiotic
  • Computational model
  • Peptidoglycan
  • Regulatory network
  • Resistance network

ASJC Scopus subject areas

  • Microbiology
  • Physiology
  • Biochemistry
  • Ecology, Evolution, Behavior and Systematics
  • Modelling and Simulation
  • Molecular Biology
  • Genetics
  • Computer Science Applications

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