Inflammation adversely affects the health of millions of people worldwide and there is an unmet medical need for better anti-inflammatory drugs. Our group evaluates the therapeutic interest of mycolactone, a polyketide-derived macrolide produced by Mycobacterium ulcerans, and simplified versions of this compound synthesized by the team of Nicolas Blanchard (University of Strasbourg, CNRS).
Infection with M. ulcerans causes ulcerative lesions of the skin that are characterized by a lack of inflammation and pain. Experiments in cell and animal models have shown that mycolactone released by the bacteria colonizing the skin is the cause of skin ulceration, and of defective inflammatory responses. In an attempt to isolate the structural determinants of mycolactone’s immunomodulatory activity, we screened a library of synthetic subunits of mycolactone for inhibition of inflammatory mediator production by immune cells. We identified truncated versions of mycolactone retaining its immunosuppressive activity relatively better than its cytotoxicity. One of them showed inhibitory activity on the production of inflammatory cytokines by human primary cells at non-cytotoxic doses in vitro. Moreover, it was considerably less toxic than natural mycolactone in human primary dermal fibroblasts modeling its ulcerative activity. In mouse models of human diseases, both mycolactone and synthetic surrogate conferred systemic protection against chronic skin inflammation and inflammatory pain, with no apparent side effects.
This study established the systemic anti-inflammatory potency of mycolactone, and highlighted the translational potential of mycolactone core-derived structures as prospective immunosuppressants. Building on these data, we now plan to analyze the activity of new mycolactone variants in vitro, and evaluate their interest in other models of inflammatory disorders and pain.