This work contributes to an emerging field in biology, which aims to comprehend the real function of microbial 'secondary' metabolites in nature. We describe how identifying elicitors regulating the biosynthesis of microbial compounds is a promising approach to uncover the many roles of these compounds, and thus highlight novel life style concepts.
We utilized this approach to bring to light alternative biological functions exerted by iron-chelating molecules called siderophores produced by the bacterial Gram-positive model organism Streptomyces coelicolor. Indeed, this methodology enabled us to unveil an unexpected relationship between these iron chelators and the cell wall component N-acetylglucosamine (GlcNAc). In the first part of this thesis, we challenge the authoritative dogma which holds that regulation of siderophore biosynthesis is inextricably tied to iron availability. Indeed, we identified an unsuspected regulatory pathway which is, to our knowledge, the first complete description of a regulatory mechanism of siderophore biosynthesis totally independent of environmental concentrations of iron.
In the second chapter of this work, we propose an evolutionary-oriented explanation for this regulatory mechanism. Our results have led us to propose a model according to which GlcNAc-induced repression of siderophore biosynthesis is required for S. coelicolor to reach the later stages of its developmental program, i.e. antibiotic production and sporulation. We speculate that siderophore-mediated iron uptake is mandatory for S. coelicolor to enter an apoptotic-like programmed cell death (PCD) process that is essential for proper differentiation. Indeed, we hypothesize that PCD is triggered by iron overload. As GlcNAc is released during PCD, we hypothesize that this preset GlcNAc-dependent iron deprivation is crucial for S. coelicolor to resume growth and access further developmental stages by shutting down iron auto-poisoning.
In the last part of this work, we further demonstrate the importance of iron in morphological and physiological differentiation of Streptomyces species. We emphasize that this element is capable of modulating the biosynthesis of bioactive compounds in streptomycetes. We singled out an unidentified Strepromyces strain, Streptomyces sp. G2, which features an increased ability to inhibit the growth of several bacteria in presence of iron. We characterized S. sp. G2 as well as the compound responsible its very potent antibacterial activity.