Mycolactones and Buruli Ulcer
Mycolactones form a family of complex macrolides that are produced by different strains of Mycobacterium ulcerans. Of these, mycolactones A/B are the causative agents for Buruli ulcer, a necrotizing skin disease with a high prevalence in sub-Saharan Africa. We have developed a new, RCM-based total synthesis of these complex macrolactones and a number of non-natural analogs to provide pure and well characterized material for biological studies (collaboration with Prof. G. Pluschke, Swiss Tropical and Public Health Institute). In addition, we have prepared a number of conjugates of the full mycolactone structure and of mycolactone partial structures that have been employed as tools for biological target identification and for the generation of antibodies and antisera. As a particular highlight of this work, using such constructs our collaborators at the Swiss TPH have been able to identify mTOR as one of the molecular targets of mycolactones A/B.
Selected reading:
Bieri, R., Scherr, N., Ruf, M.-T., Dangy, J.-P., Gersbach, P., Gehringer, M., Altmann, K.-H., Pluschke, G. The Macrolide Toxin Mycolactone Promotes Bim-Dependent Apoptosis in Buruli Ulcer through Inhibition of mTOR. ACS Chemical Biology 2017, 12, 1297-1307.
Dangy, J.-P., Scherr, N., Gersbach, P., Hug, M. N., Bieri, R., Huber, S., Bomio, C., Li, J., Altmann, K.-H., Pluschke, G. Antibody-Mediated Neutralization of the Exotoxin Mycolactone, the Main Virulence Factor Produced by Mycobacterium ulcerans. PLoS Negl. Trop. Dis. 2016, 10, e0004808.
Scherr, N., Gersbach, P., Dangy, J.-P., Bomio, C., Li, J., Altmann, K.-H., Pluschke, G. Structure-Activity Relationship Studies on the Macrolide Exotoxin Mycolactone of Mycobacterium ulcerans. PLOS Neglect. Trop. D. 2013, 7, e2143.
Gersbach, P., Jantsch, A., Feyen, F., Scherr, N., Dangy, J.-P., Pluschke, G., Altmann, K.-H. A Ring-Closing Metathesis (RCM)-Based Approach to Mycolactones A/B. Chemistry Eur. J. 2011, 17, 13017-13031.