Computational insights into promoter architecture of toxin-antitoxin systems of Mycobacterium tuberculosis

Toxin-antitoxin (TA) systems are two component genetic modules widespread in many bacterial genomes, including Mycobacterium tuberculosis (Mtb). The TA systems play a significant role in biofilm formation, antibiotic tolerance and persistence of pathogen inside the host cells. Deciphering regulatory motifs of Mtb TA systems is the first essential step to understand their transcriptional regulation. In this study, in silico approaches, that is, the knowledge based motif discovery and de novo motif discovery were used to identify the regulatory motifs of 79 Mtb TA systems. The knowledge based motif discovery approach was used to design a Perl based bio-tool Mtb-sig-miner available at (https://github.com/zoozeal/Mtb-sig-miner), which could successfully detect sigma (σ) factor specific regulatory motifs in the promoter region of Mtb TA modules. The manual curation of Mtb-sig-miner output hits revealed that the majority of them possessed σ^B regulatory motif in their promoter region. On the other hand, de novo approach resulted in the identification of a novel conserved motif [(T/A)(G/T)NTA(G/C)(C/A)AT(C/A)] within the promoter region of 14 Mtb TA systems. The identified conserved motif was also validated for its activity as conserved core region of operator sequence of corresponding TA system by molecular docking studies. The strong binding of respective antitoxin/toxin with the identified novel conserved motif reflected the validation of identified motif as the core region of operator sequence of respective TA systems. These findings provide computational insight to understand the transcriptional regulation of Mtb TA systems.