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Resistance to bacitracin in Bacillus subtilis: unexpected requirement of the BceAB ABC transporter in the control of expression of its own structural genes.

ABSTRACT: The Bacillus subtilis BceAB ABC transporter involved in a defense mechanism against bacitracin is composed of a membrane-spanning domain and a nucleotide-binding domain. Induction of the structural bceAB genes requires the BceR response regulator and the BceS histidine kinase of a signal transduction system. However, despite the presence of such a transduction system and of bacitracin, no transcription from an unaltered bceA promoter is observed in cells lacking the BceAB transporter. Expression in trans of the BceAB transporter in these bceAB cells restores the transcription from the bceA promoter. Cells possessing a mutated nucleotide-binding domain of the transporter are also no longer able to trigger transcription from the bceA promoter in the presence of bacitracin, although the mutated ABC transporter is still bound to the membrane. In these cells, expression of the bceA promoter can no longer be detected, indicating that the ABC transporter not only must be present in the cell membrane, but also must be expressed in a native form for the induction of the bceAB genes. Several hypotheses are discussed to explain the simultaneous need for bacitracin, a native signal transduction system, and an active BceAB ABC transporter to trigger transcription from the bceA promoter.

SUBMITTER: Bernard R

PROVIDER: S-EPMC2168949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Resistance to bacitracin in Bacillus subtilis: unexpected requirement of the BceAB ABC transporter in the control of expression of its own structural genes.

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