Sébastien Rigali
Maître de Recherche FNRS
Linking environmental signals to the bacterial developmental response
A central theme in modern microbiology is understanding how microorganisms adapt their specialized metabolism in response to environmental cues. Gaining such insight is also key to uncovering novel molecules encoded by the vast repertoire of cryptic biosynthetic gene clusters (BGCs).
What specific environmental signals trigger specialized metabolism in streptomycetes, and through which molecular mechanisms are these signals conveyed to the bacterial developmental program?
Addressing these fundamental questions is the primary research focus of the Strepto Team at ULiège. Some of the published pathways discovered by our group are presented in the provided figure.
More signalling pathways will be discovered in the near future thanks to our new bioinformatic tool "COMMBAT".
Pathways from carbon source transport to activation/repression of specialized metabolite biosynthesis. A. The GlcNAc-mediated control of prodiginine, actinorhodin and siderophore production mediated by DasR in S. coelicolor. B. The CebR/cello-oligosaccharide-mediated control of thaxtomin production in the plant pathogen S. scabiei.
Our NEW web tool designed to predict transcription factors — and their associated environmental signals — that regulate the expression of bacterial biosynthetic gene clusters (BGCs).
Cave Microbiology - Natural Product Discovery
The decision of our laboratory to search for antibiotic-producing bacteria in moonmilk deposits originated from evidence of hundreds of years of mining activities for the use of this speleothem as powder with antimicrobial properties. The first scanning electron micrographs of the calcite fibers of moonmilk also revealed filamentous bacteria further supporting the presence of microorganisms notorious as ‘antibiotic-makers’. Indeed, each actinomycete we isolated from three different moonmilk deposits of the cave ‘la grotte des collemboles’ (Comblain-au-Pont, Belgium) displayed antibacterial and/or antifungal activities. Strains of Streptomyces lunaelactis have been found in all moonmilk deposits of the cave and genome mining revealed that these strains are a remarkable example of a species with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs). BGC 28a is one of the cryptic BGCs that is only carried by a subgroup of S. lunaelactis strains for which in silico analysis predicted the production of nonribosomal peptide antibiotics containing the non-proteogenic amino acid piperazic acid (Piz). Comparative metabolomics of culture extracts of S. lunaelactis strains either holding or not holding BGC 28a combined with MS/MS-guided peptidogenomics and 1H/13C NMR allowed us to identify the cyclic hexapeptide with the amino acid sequence (D-Phe)-(L-HO-Ile)-(D-Piz)-(L-Piz)-(D-Piz)-(L-Piz), called lunaemycin A, as the main compound synthesized by BGC 28a. Molecular networking further identified 18 additional lunaemycins, with 14 of them having their structure elucidated by HRMS/MS. Antimicrobial assays demonstrated a significant bactericidal activity of lunaemycins against Gram-positive bacteria, including multi-drug resistant clinical isolates. Our work demonstrates how an accurate in silico analysis of a cryptic BGC can highly facilitate the identification, the structural elucidation, and the bioactivity of its associated specialized metabolites..
Common scab and genetic and physiology of Streptomyces scabiei
Our group has significantly advanced the understanding of how Streptomyces scabiei, the causative agent of common scab in root and tuber crops, senses and responds to host plant signals to initiate pathogenicity. We identified cellotriose, as the primary elicitor of the expression of virulence genes. This signal is transported via the CebEFG–MsiK ABC transporter system, and its uptake relieves repression by the CebR regulator, thereby activating the production of thaxtomin A, the main phytotoxin.We also solved the crystal structure of CebE bound to cellotriose, providing structural insight into how this pathogen detects host-derived cues with high specificity.Beyond thaxtomin, metabolomic and transcriptomic analyses revealed that cellotriose induces a broader “virulome” including concanamycin, siderophores (e.g., desferrioxamines, scabichelin, turgichelin), ectoine, and antimicrobial compounds like bottromycin, while repressing germicidins, which inhibit spore germination.
