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Background  Carolacton is a newly identified secondary metabolite causing altered cell morphology and death of  Streptococcus mutans  biofilm cells. To unravel key regulators mediating these effects, the transcriptional regulatory response network of  S. mutans  biofilms upon carolacton treatment was constructed and analyzed. A systems biological approach integrating time-resolved transcriptomic data, reverse engineering, transcription factor binding sites, and experimental validation was carried out.    Results  The co-expression response network constructed from transcriptomic data using the reverse engineering algorithm called the Trend Correlation method consisted of 8284 gene pairs. The regulatory response network inferred by superimposing transcription factor binding site information into the co-expression network comprised 329 putative transcriptional regulatory interactions and could be classified into 27 sub-networks each co-regulated by a transcription factor. These sub-networks were significantly enriched with genes sharing common functions. The regulatory response network displayed global hierarchy and network motifs as observed in model organisms. The sub-networks modulated by the pyrimidine biosynthesis regulator PyrR, the glutamine synthetase repressor GlnR, the cysteine metabolism regulator CysR, global regulators CcpA and CodY and the two component system response regulators VicR and MbrC among others could putatively be related to the physiological effect of carolacton. The predicted interactions from the regulatory network between MbrC, known to be involved in cell envelope stress response, and the  murMN -SMU_718c genes encoding peptidoglycan biosynthetic enzymes were experimentally confirmed using Electro Mobility Shift Assays. Furthermore, gene deletion mutants of five predicted key regulators from the response networks were constructed and their sensitivities towards carolacton were investigated. Deletion of  cysR , the node having the highest connectivity among the regulators chosen from the regulatory network, resulted in a mutant which was insensitive to carolacton thus demonstrating not only the essentiality of  cysR  for the response of  S. mutans  biofilms to carolacton but also the relevance of the predicted network.    Conclusion  The network approach used in this study revealed important regulators and interactions as part of the response mechanisms of  S. mutans  biofilm cells to carolacton. It also opens a door for further studies into novel drug targets against streptococci.    Electronic supplementary material  The online version of this article (doi:10.1186/1471-2164-15-362) contains supplementary material, which is available to authorized users.

bmc genomics

Construction and verification of the transcriptional regulatory response network of Streptococcus mutansupon treatment with the biofilm inhibitor carolacton