A Diverted Total Synthesis of Mycolactone Analogues: An Insight into Buruli Ulcer Toxins

Chany, Anne‐Caroline; Casarotto, Virginie; Schmitt, Marjorie; Tarnus, Céline; Guenin-Macé, Laure; Demangel, Caroline; Mirguet, Olivier; Eustache, Jacques; Blanchard, Nicolas

doi:10.1002/chem.201102542

Cited by 61 publications

(99 citation statements)

References 59 publications

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“…33 The present results demonstrate that 4b is only 3-fold less efficient for the binding to WASP, with an IC 50 of 97.5 ± 7.1 μM vs 32.3 ± 22.1 μM for natural mycolactone A/B ( Figure 5B and Figure 6). Compared to 5b (IC 50 = 21.5 ± 0.7 μM), addition of a (triazol-4-yl)ethanol to the core in northern position (32c) limited binding (IC 50 = 170 μM), as did the selective epimerization of C12′ and C15′ (5i, IC 50 = 100 μM) or the removal of two hydroxyl groups of the southern fragment (C13′,C15′-dideoxy 5m, IC 50 = 350 ± 70.7 μM) or one hydroxyl group in C15′ (5k, IC 50 = 250 ± 0.7 μM).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 69%

“…25 The chemical synthesis of natural products and their derivatives allows the biological exploration of complex systems, and programs centered on the synthesis and structural modulation of mycolactone A/B have been reported by Kishi, Altmann, and us ( Figure 2). 2 Kishi clearly opened the way to chemical modifications of this exotoxin with several generations of elegant total syntheses of mycolactone A/B and also of the 33 other eight naturally occurring mycolactones that differ only by the nature of the southern fragment. 2,9,26−30 However, the cytopathic effect (CPE, the concentration of mycolactone analogue for which 90% of the cells round up) of only the single analogue 1a was disclosed up to now (Figure 2A).…”

Section: ■ Introductionmentioning

confidence: 98%

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Synthetic Variants of Mycolactone Bind and Activate Wiskott–Aldrich Syndrome Proteins

et al. 2014

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Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott-Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 69%

Section: ■ Introductionmentioning

confidence: 98%

Synthetic Variants of Mycolactone Bind and Activate Wiskott–Aldrich Syndrome Proteins

et al. 2014

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“…Bodipy-labelled mycolactone has been detected in the cytosol of cells within 2 minutes of exposure, but interestingly is excluded from the nucleus [24,25]. Other in vivo experiments have demonstrated that mycolactone can diffuse away from the site of injection and can access all bodily compartments with the exception of the brain [26].…”

Section: Mycolactonementioning

confidence: 89%

Pleiotropic molecular effects of theMycobacterium ulceransvirulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer

Hall

Simmonds

2014

Biochemical Society Transactions

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Mycolactone is a polyketide macrolide lipid-like secondary metabolite synthesised by Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), and is the only virulence factor for this pathogen identified to date. Prolonged exposure to high concentrations of mycolactone is cytotoxic to diverse mammalian cells (albeit with varying efficiency), whereas at lower doses it has a spectrum of immunosuppressive activities. Combined, these pleiotropic properties have a powerful influence on local and systemic cellular function that should explain the pathophysiology of BU disease. The past decade has seen significant advances in our understanding of the molecular mechanisms underlying these effects in a range of different cell types. This review will focus on the current state of our knowledge of mycolactone function, its molecular and cellular targets, seeking to identify commonalities between the different functional and cellular systems. Since mycolactone influences fundamental cellular processes (cell division, cell death, and inflammation), getting to the root of how mycolactone achieves this could have profound impact on our understanding of eukaryotic cell biology.

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“…Modular variants of mycolactone were synthesized as described (20,23). Stock solutions of mycolactone and variants were prepared in dimethyl sulfoxide, and then diluted 1000× in culture medium for cellular assays or 10× in PBS before injection in animals.…”

Section: Methodsmentioning

confidence: 99%

Shaping mycolactone for therapeutic use against inflammatory disorders

et al. 2015

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Inflammation adversely affects the health of millions of people worldwide, and there is an unmet medical need for better anti-inflammatory drugs. We evaluated the therapeutic interest of mycolactone, a polyketide-derived macrolide produced by Mycobacterium ulcerans. Bacterial production of mycolactone in human skin causes a combination of ulcerative, analgesic, and anti-inflammatory effects. Whereas ulcer formation is mediated by the proapoptotic activity of mycolactone on skin cells via hyperactivation of Wiskott-Aldrich syndrome proteins, analgesia results from neuronal hyperpolarization via signaling through angiotensin II type 2 receptors. Mycolactone also blunts the capacity of immune cells to produce inflammatory mediators by an independent mechanism of protein synthesis blockade. In an attempt to isolate the structural determinants of mycolactone's immunosuppressive activity, we screened a library of synthetic subunits of mycolactone for inhibition of cytokine production by activated T cells. The minimal structure retaining immunosuppressive activity was a truncated version of mycolactone, missing one of the two core-branched polyketide chains. This compound inhibited the inflammatory cytokine responses of human primary cells at noncytotoxic doses and bound to angiotensin II type 2 receptors comparably to mycolactone in vitro. Notably, it was considerably less toxic than mycolactone in human primary dermal fibroblasts modeling ulcerative activity. In mouse models of human diseases, it conferred systemic protection against chronic skin inflammation and inflammatory pain, with no apparent side effects. In addition to establishing the anti-inflammatory potency of mycolactone in vivo, our study therefore highlights the translational potential of mycolactone core-derived structures as prospective immunosuppressants.

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A Diverted Total Synthesis of Mycolactone Analogues: An Insight into Buruli Ulcer Toxins

Cited by 61 publications

References 59 publications

Synthetic Variants of Mycolactone Bind and Activate Wiskott–Aldrich Syndrome Proteins

Synthetic Variants of Mycolactone Bind and Activate Wiskott–Aldrich Syndrome Proteins

Pleiotropic molecular effects of theMycobacterium ulceransvirulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer

Shaping mycolactone for therapeutic use against inflammatory disorders

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