mycolactone-b and Buruli-Ulcer

Mycobacterium ulcerans infections (Buruli ulcer disease) have a long history that can be traced back 150 years. The successive discoveries of the mycobacteria in 1948 and of mycolactone A/B in 1999, the toxin responsible for this dramatic necrotic skin disease, resulted in a paradigm shift concerning the disease itself and in a broader sense, delineated an entirely new role for bioactive polyketides as virulence factors. The fascinating history, biology and chemistry of M. ulcerans infections are discussed in this review.

Topics: Buruli Ulcer; History, 20th Century; Humans; Macrolides; Molecular Structure

Buruli ulcer, classified as a neglected tropical disease by the World Health Organization, is caused by a mycobacterium which secretes a macrolidic exotoxin called mycolactone A/B. In this article, several synthetic strategies for the preparation of this toxin are discussed, highlighting the importance of total synthesis for the exploration of biological mechanism underpinning relevant human diseases.

Topics: Buruli Ulcer; Humans; Macrolides

The pathogenicity of Mycobacterium ulcerans (Buruli ulcer) is closely associated with the secretion of exotoxin mycolactone. The cytotoxicity of mycolactone has been linked to its apoptogenic activity. We explored if low mycolactone concentrations, which are not able to induce apoptosis, can influence other essential activities on two primary human keratinocyte populations, keratinocyte stem cells (KSC) and transit amplifying cells (TAC), and on a human keratinocyte line, HaCaT. We demonstrated that 0.01 and 0.1 ng/ml mycolactone A/B are not able to induce apoptosis in primary human keratinocytes, but interfere with KSC wound repair. Moreover, the same toxin concentrations reduce cell proliferation of KSC and TAC and their ability to adhere to type IV collagen. HaCaT cells are more resistant to the toxin; nevertheless, they show a delayed woud repair when treated with 1 and 10 ng/ml mycolactone A/B. Moreover, these sub-apoptotic concentrations affect their ability to proliferate and adhere to collagen IV. Wound healing is a complex mechanism, which occurs "in vivo" as the outcome of many co-ordinated events. Sub-apoptotic mycolactone concentrations can affect essential mechanisms, which are required to achieve wound repair, such as adhesion, migration and proliferation of human keratinocytes.

Topics: Adult; Apoptosis; Buruli Ulcer; Cell Adhesion; Cell Line; Cell Proliferation; Collagen Type IV; Humans; Keratinocytes; Macrolides; Middle Aged; Mycobacterium ulcerans; Stem Cells; Wound Healing

Photochemistry of mycolactone A/B and related unsaturated fatty acid esters is reported. On exposure to visible light, mycolactone A/B gave a mixture of four photomycolactones. Pentaenoates and tetraenoates, representing the unsaturated fatty acid portion of mycolactone A/B, were found to show the reactivity profile parallel with that of mycolactone A/B. The structure of the four photomycolactones was elucidated via (1) structure determination of the four photoproducts in the tetraenoate series; (2) their transformation to the photoproducts in the pentaenoate and then mycolactone series. Triplet quenchers did not affect the photochemical transformation, thereby indicating an event at the singlet state. A concerted, photochemically allowed [4πs + 2πa] cycloaddition was suggested to account for the observed result. This study provided the structurally defined and homogeneous material, which allowed demonstration that photomycolactones exhibit significantly reduced cytotoxicity, compared with mycolactone A/B.

Topics: Buruli Ulcer; Humans; Macrolides; Molecular Structure; Photochemical Processes; Stereoisomerism

Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.

Topics: Animals; Bacterial Toxins; Buruli Ulcer; Fibroblasts; Macrolides; Mice; Molecular Structure; Mycobacterium Infections; Mycobacterium ulcerans; Structure-Activity Relationship