From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>

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. H...

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Autores principales:	Hannah Piepenbreier, Andre Sim, Carolin M. Kobras, Jara Radeck, Thorsten Mascher, Susanne Gebhard, Georg Fritz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	cell wall antibiotic antimicrobial peptide bacitracin peptidoglycan resistance network regulatory network Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dce2776f057b47daa26e0cb5a1ecc32f
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spelling	oai:doaj.org-article:dce2776f057b47daa26e0cb5a1ecc32f2021-12-02T18:44:38ZFrom Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>10.1128/mSystems.00687-192379-5077https://doaj.org/article/dce2776f057b47daa26e0cb5a1ecc32f2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00687-19https://doaj.org/toc/2379-5077ABSTRACT 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.Hannah PiepenbreierAndre SimCarolin M. KobrasJara RadeckThorsten MascherSusanne GebhardGeorg FritzAmerican Society for Microbiologyarticlecell wall antibioticantimicrobial peptidebacitracinpeptidoglycanresistance networkregulatory networkMicrobiologyQR1-502ENmSystems, Vol 5, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	cell wall antibiotic antimicrobial peptide bacitracin peptidoglycan resistance network regulatory network Microbiology QR1-502
spellingShingle	cell wall antibiotic antimicrobial peptide bacitracin peptidoglycan resistance network regulatory network Microbiology QR1-502 Hannah Piepenbreier Andre Sim Carolin M. Kobras Jara Radeck Thorsten Mascher Susanne Gebhard Georg Fritz From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>
description	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.
format	article
author	Hannah Piepenbreier Andre Sim Carolin M. Kobras Jara Radeck Thorsten Mascher Susanne Gebhard Georg Fritz
author_facet	Hannah Piepenbreier Andre Sim Carolin M. Kobras Jara Radeck Thorsten Mascher Susanne Gebhard Georg Fritz
author_sort	Hannah Piepenbreier
title	From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>
title_short	From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>
title_full	From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>
title_fullStr	From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>
title_full_unstemmed	From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>
title_sort	from modules to networks: a systems-level analysis of the bacitracin stress response in <named-content content-type="genus-species">bacillus subtilis</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/dce2776f057b47daa26e0cb5a1ecc32f
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From Modules to Networks: a Systems-Level Analysis of the Bacitracin Stress Response in <named-content content-type="genus-species">Bacillus subtilis</named-content>

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