title: Shaping mycolactone for therapeutic use against inflammatory disorders.
abstract: 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.
authors.affiliation: Institut Pasteur, Unité d'Immunobiologie de l'Infection, Paris 75015, France. CNRS URA 1961, Paris 75015, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Guenin-Macé
authors.affiliation: Institut Pasteur, Unité d'Immunobiologie de l'Infection, Paris 75015, France. CNRS URA 1961, Paris 75015, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Baron
authors.affiliation: Université de Strasbourg, Laboratoire de Chimie Moléculaire, ECPM-CNRS UMR 7509, Strasbourg 67087, France.
authors.forename: Anne-Caroline
authors.initials: AC
authors.lastname: Chany
authors.affiliation: Université de Strasbourg, Laboratoire de Chimie Moléculaire, ECPM-CNRS UMR 7509, Strasbourg 67087, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Tresse
authors.affiliation: Université de Strasbourg, Laboratoire de Chimie Moléculaire, ECPM-CNRS UMR 7509, Strasbourg 67087, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Saint-Auret
authors.affiliation: Institut Pasteur, Unité Anticorps en Thérapie et Pathologie, Paris 75015, France. INSERM U760, Paris 75015, France.
authors.forename: Friederike
authors.initials: F
authors.lastname: Jönsson
authors.affiliation: Institut Pasteur, Unité d'Immunobiologie de l'Infection, Paris 75015, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Le Chevalier
authors.affiliation: Institut Pasteur, Unité Anticorps en Thérapie et Pathologie, Paris 75015, France. INSERM U760, Paris 75015, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bruhns
authors.affiliation: INSERM U1016, Institut Cochin, Paris 75014, France. Université Paris Descartes, Paris 75014, France. CNRS UMR 8104, Paris 75014, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Bismuth
authors.affiliation: ETAP, Inflammation, Dermatologie et Toxicologie, Vandœuvre-lès-Nancy 54500, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hidalgo-Lucas
authors.affiliation: ETAP, Inflammation, Dermatologie et Toxicologie, Vandœuvre-lès-Nancy 54500, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bisson
authors.affiliation: Université de Strasbourg, Laboratoire de Chimie Moléculaire, ECPM-CNRS UMR 7509, Strasbourg 67087, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchard
authors.affiliation: Institut Pasteur, Unité d'Immunobiologie de l'Infection, Paris 75015, France. CNRS URA 1961, Paris 75015, France. demangel@pasteur.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Demangel
mesh_terms: D000818:Animals; D002908:Chronic Disease; D006367:HeLa Cells; D006801:Humans; D056747:Immunomodulation; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D019169:Jurkat Cells; D018942:Macrolides / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D019911:Mycobacterium ulcerans / Q000502:physiology; D010146:Pain / Q000150:complications / Q000188:drug therapy; D020011:Protective Agents / Q000627:therapeutic use; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D018942:Macrolides; D020011:Protective Agents; C117218:mycolactone; D013755:Tetradecanoylphorbol Acetate