Motivation behind the research
Buruli ulcer is a severe and devastating skin disease in humans currently reported in more than 30 countries. Several thousand people are infected each year, especially in tropical Africa and Oceania, where Buruli ulcers are often a source of major disability. Since the clinical description of this third most common mycobacterial disease in 1948, intense research efforts have been deployed by the scientific community leading to the demonstration that the disease is due to Mycobacterium ulcerans, a microorganism which secretes an exotoxin called mycolactone A/B. In a unique manner, this exotoxin is responsible for all the pathogenic effects observed during the infection and consisting in a necrosis of tissue combined with an absence of immune response and a lack of pain. The discovery of mycolactone A/B in 1999 was a breakthrough as it opened a molecular perspective on this devastating disease, although to date no specific treatment (besides the combination of antibiotics recommended by the WHO) or early diagnosis have been developed because of the unawareness of the associated chemical and biological mechanisms of the disease.
Since 2006, in close collaboration with a team of immunologists from the Institut Pasteur (Paris, France) we have been engaged in the laboratory preparation of mycolactone A/B analogues that led us to report some structure-activity relationship (SAR) data and to uncover the therapeutic potential of mycolactone A/B (obtained from culture of the mycobacterium) and its analogues. The modular synthetic scheme is of prime importance to further advance our understanding by providing tailored-made tools to explore the biology of the disease.
For the past three years, we have investigated a new way of preparing mycolactone A/B in the laboratory. The added value of this synthetic scheme is the possibility to prepare the natural toxin itself (as an inconsequential mixture of isomers from a biological point of view) but also some analogues at a very late stage of the work, with minimal deviations. Such modifications are currently not possible with existent strategies of preparation of mycolactone A/B. For example, we have shown that an isotopically-labelled mycolactone A/B could be prepared and could potentially be used as a reference during quantification of the toxin in biological tissues.
Even if this new way of preparing mycolactone A/B in the laboratory led to sufficient quantities for biological investigations, two shortcomings still exist. Indeed, it would be desirable to design a way of preparing the toxin without any mixture of isomers (even if this is demonstrated to have no impact on the biological activity), while maintaining the possibility of performing late-stage modification of the molecule. In addition, this late-stage modification should be explored more thoroughly with the introduction of fluorescent and/or reactive tags for example.
Considering the therapeutic potential of mycolactone A/B and its analogues, this work opens new perspectives for the late-stage modification of advanced mycolactone intermediates and the preparation of tools to explore the biology of the disease. Therefore, future work will focus on the synthesis of specific probes based on the mycolactone A/B chemical structure which could help the scientific community to decipher the biology of this complex disease and ultimately to develop rational diagnostic and therapeutic tools.
Research Article: Modular total syntheses of mycolactone A/B and its [²H]-isotopologue. Organic and Biomolecular Chemistry, 2017.