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Background Mycobacterium ulcerans, a slow-growing environmental bacterium, is the etiologic agent of Buruli ulcer, a necrotic skin disease. Skin lesions are caused by mycolactone, the main virulence factor of M. ulcerans, with dermonecrotic (destruction of the skin and soft tissues) and immunosuppressive activities. This toxin is secreted in vesicles that enhance its biological activities. Nowadays, it is well established that the main reservoir of the bacilli is localized in the aquatic environment where the bacillus may be able to colonize different niches. Here we report that plant polysaccharides stimulate M. ulcerans growth and are implicated in toxin synthesis regulation. Methodology/Principal Findings In this study, by selecting various algal components, we have identified plant-specific carbohydrates, particularly glucose polymers, capable of stimulating M. ulcerans growth in vitro. Furthermore, we underscored for the first time culture conditions under which the polyketide toxin mycolactone, the sole virulence factor of M. ulcerans identified to date, is down-regulated. Using a quantitative proteomic approach and analyzing transcript levels by RT-qPCR, we demonstrated that its regulation is not at the transcriptional or translational levels but must involve another type of regulation. M. ulcerans produces membrane vesicles, as other mycobacterial species, in which are the mycolactone is concentrated. By transmission electron microscopy, we observed that the production of vesicles is independent from the toxin production. Concomitant with this observed decrease in mycolactone production, the production of mycobacterial siderophores known as mycobactins was enhanced. Conclusions/Significance This work is the first step in the identification of the mechanisms involved in mycolactone regulation and paves the way for the discovery of putative new drug targets in the future., Author Summary Mycolactone, a polyketide cytotoxic toxin, is the key virulence factor responsible for large skin ulcers in Buruli ulcer. This disease, mainly occurring in humid tropical zones, especially in West African countries, is due to infection by Mycobacterium ulcerans, a slow-growing environmental mycobacterium. The toxin has destructive effects on the skin, soft tissues and bones. In this study, we brought out for the first time that addition of specific carbohydrate to culture medium induces the down-regulation of the toxin. Furthermore, this decrease in toxin production is correlated with the activation of the iron acquisition pathway, especially by siderophore production. These results show that M. ulcerans adapts its metabolism to culture conditions, which probably reflect its adaptation in its natural habitats. This work is the first step in toxin regulation understanding which is a key issue for a better comprehension of Buruli ulcer physiopathology and the identification of putative therapeutic targets.