Development and application of the COMMBAT tool linking environmental signals to the expression control of BGCs in microorganisms

It is nowadays commonly accepted that known microbial natural products only constitute a small fraction of bioactive compounds in the microbial world. Many of them are not produced under laboratory conditions and a main challenge is to identify the molecular mechanisms involved in the transcriptional control of the biosynthetic gene clusters (BGCs). What are the environmental cues that trigger the specialized metabolism of bacteria and with which molecular mechanisms these molecules transmit the message to the bacterial developmental program? To answer these questions, bioinformatic tools are being developed and applied to unveil new signaling pathways of known or cryptic specialized metabolisms.

The main objective is to contribute to setting up an automated methodology for fast, reliable, and exhaustive identification of BGCs – either cryptic or associated with known natural products – whose expression responds to a specific environmental cue. The methodology named COMMBAT (COnditions for Microbial Metabolite Biosynthesis Activated Transcription), is based on the detection of cis-acting elements bound by a transcription factor of interest in BGCs. The methodology is divided into four main steps: 1) Creation/Selection of a position weight matrix (PWM) of a transcription factor's cis-acting elements; 2) Selection of BGCs to analyze (either BGCs that were identified from downloaded genome sequences or known BGCs from the MIBiG database); 3) Scan of the BGCs with the PWM created at step 1; 4) Analysis of the output generated at step 3 to identify BGCs (either known or cryptic) that would reliably respond to a specific environmental signal.

The COMMBAT tool can have several applications. It can identify the regulator of a known or unknown BGC and the tool can also be used to predict the extent to which a regulation pathway is conserved amongst several species. In addition, the tool will calculate a COMMBAT score that considers the relative position of the binding site to the gene and the gene kind. This score will determine how likely the found binding site of a regulator is going to control the production of the BGC's metabolites. Furthermore, an online version of the COMMBAT tool is in development and a demonstration of this online tool will be made during the presentation.