From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in Bacillus subtilis
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Hannah Piepenbreier
- Andre Sim
- Carolin M Kobras
- Jara Radeck
- Thorsten Mascher
- Susanne Gebhard
- Georg Fritz
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000518855000036&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1128/mSystems.00687-19
- Externe Identifier
- Clarivate Analytics Document Solution ID: KT2OI
- PubMed Identifier: 32019833
- ISSN
- 2379-5077
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- MSYSTEMS
- Schlüsselwörter
- cell wall antibiotic
- antimicrobial peptide
- bacitracin
- peptidoglycan
- resistance network
- regulatory network
- computational model
- antibiotic resistance
- Artikelnummer
- ARTN e00687-19
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Titel
- From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <i>Bacillus subtilis</i>
- Sub types
- Article
- Ausgabe der Zeitschrift
- 5
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p> Antibiotic resistance poses a major threat to global health, and systematic studies to understand the underlying resistance mechanisms are urgently needed. Although significant progress has been made in deciphering the mechanistic basis of individual resistance determinants, many bacterial species rely on the induction of a whole battery of resistance modules, and the complex regulatory networks controlling these modules in response to antibiotic stress are often poorly understood. In this work we combined experiments and theoretical modeling to decipher the resistance network of <jats:named-content content-type="genus-species">Bacillus subtilis</jats:named-content> against bacitracin, which inhibits cell wall biosynthesis in Gram-positive bacteria. We found a high level of cross-regulation between the two major resistance modules in response to bacitracin stress and quantified their effects on bacterial resistance. To rationalize our experimental data, we expanded a previously established computational model for the lipid II cycle through incorporating the quantitative action of the resistance modules. This led us to a systems-level description of the bacitracin stress response network that captures the complex interplay between resistance modules and the essential lipid II cycle of cell wall biosynthesis and accurately predicts the minimal inhibitory bacitracin concentration in all the studied mutants. With this, our study highlights how bacterial resistance emerges from an interlaced network of redundant homeostasis and stress response modules. </jats:p>
- Autoren
- Hannah Piepenbreier
- Andre Sim
- Carolin M Kobras
- Jara Radeck
- Thorsten Mascher
- Susanne Gebhard
- Georg Fritz
- DOI
- 10.1128/msystems.00687-19
- Editoren
- Domitilla Del Vecchio
- eISSN
- 2379-5077
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- mSystems
- Sprache
- en
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Herausgeber
- American Society for Microbiology
- Herausgeber URL
- http://dx.doi.org/10.1128/msystems.00687-19
- Datum der Datenerfassung
- 2022
- Titel
- From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in Bacillus subtilis
- Ausgabe der Zeitschrift
- 5
Data source: Crossref
- 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 <i>Bacillus subtilis</i> 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 <i>B. subtilis</i> 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.<b>IMPORTANCE</b> Antibiotic resistance poses a major threat to global health, and systematic studies to understand the underlying resistance mechanisms are urgently needed. Although significant progress has been made in deciphering the mechanistic basis of individual resistance determinants, many bacterial species rely on the induction of a whole battery of resistance modules, and the complex regulatory networks controlling these modules in response to antibiotic stress are often poorly understood. In this work we combined experiments and theoretical modeling to decipher the resistance network of <i>Bacillus subtilis</i> against bacitracin, which inhibits cell wall biosynthesis in Gram-positive bacteria. We found a high level of cross-regulation between the two major resistance modules in response to bacitracin stress and quantified their effects on bacterial resistance. To rationalize our experimental data, we expanded a previously established computational model for the lipid II cycle through incorporating the quantitative action of the resistance modules. This led us to a systems-level description of the bacitracin stress response network that captures the complex interplay between resistance modules and the essential lipid II cycle of cell wall biosynthesis and accurately predicts the minimal inhibitory bacitracin concentration in all the studied mutants. With this, our study highlights how bacterial resistance emerges from an interlaced network of redundant homeostasis and stress response modules.
- Addresses
- LOEWE Center for Synthetic Microbiology and Department of Physics, Philipps-Universität Marburg, Marburg, Germany.
- Autoren
- Hannah Piepenbreier
- Andre Sim
- Carolin M Kobras
- Jara Radeck
- Thorsten Mascher
- Susanne Gebhard
- Georg Fritz
- DOI
- 10.1128/msystems.00687-19
- eISSN
- 2379-5077
- Externe Identifier
- PubMed Identifier: 32019833
- PubMed Central ID: PMC7002115
- Funding acknowledgements
- UK Research and Innovation | Biotechnology and Biological Sciences Research Council: BB/M029255/1
- Deutsche Forschungsgemeinschaft: FR3673/1-2
- Deutsche Forschungsgemeinschaft: MA2837/2-2
- Biotechnology and Biological Sciences Research Council: BB/M029255/1
- Open access
- true
- ISSN
- 2379-5077
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- mSystems
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2020
- Open access status
- Open Access
- Paginierung
- e00687 - e00619
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2020
- Titel
- From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in Bacillus subtilis.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 5
Files
https://msystems.asm.org/content/msys/5/1/e00687-19.full.pdf https://europepmc.org/articles/PMC7002115?pdf=render
Data source: Europe PubMed Central
- 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.IMPORTANCE Antibiotic resistance poses a major threat to global health, and systematic studies to understand the underlying resistance mechanisms are urgently needed. Although significant progress has been made in deciphering the mechanistic basis of individual resistance determinants, many bacterial species rely on the induction of a whole battery of resistance modules, and the complex regulatory networks controlling these modules in response to antibiotic stress are often poorly understood. In this work we combined experiments and theoretical modeling to decipher the resistance network of Bacillus subtilis against bacitracin, which inhibits cell wall biosynthesis in Gram-positive bacteria. We found a high level of cross-regulation between the two major resistance modules in response to bacitracin stress and quantified their effects on bacterial resistance. To rationalize our experimental data, we expanded a previously established computational model for the lipid II cycle through incorporating the quantitative action of the resistance modules. This led us to a systems-level description of the bacitracin stress response network that captures the complex interplay between resistance modules and the essential lipid II cycle of cell wall biosynthesis and accurately predicts the minimal inhibitory bacitracin concentration in all the studied mutants. With this, our study highlights how bacterial resistance emerges from an interlaced network of redundant homeostasis and stress response modules.
- Autoren
- Hannah Piepenbreier
- Andre Sim
- Carolin M Kobras
- Jara Radeck
- Thorsten Mascher
- Susanne Gebhard
- Georg Fritz
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/32019833
- DOI
- 10.1128/mSystems.00687-19
- Externe Identifier
- PubMed Central ID: PMC7002115
- ISSN
- 2379-5077
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- mSystems
- Schlüsselwörter
- antibiotic resistance
- antimicrobial peptide
- bacitracin
- cell wall antibiotic
- computational model
- peptidoglycan
- regulatory network
- resistance network
- Sprache
- eng
- Country
- United States
- PII
- 5/1/e00687-19
- Datum der Veröffentlichung
- 2020
- Status
- Published online
- Titel
- From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in Bacillus subtilis.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 5
Data source: PubMed
- Beziehungen:
- Property of