Tiacumicin B, a New Antibacterial Natural Product Lead Acting on a Novel Druggable Target – SYNTIA

Resistance to antibiotics is a serious re-emerging biomedical risk degrading the quality of life and impacting our economies. One of the most efficient solutions to fight resistances is to identify new molecules interacting with totally new biological targets, but this is a rare event. However this is the case of tiacumicin B, a naturally occurring antibiotic that received FDA approval in 2011 in the USA for treatment of the deadly nosocomial diarrhea associated to Clostridium difficile. Tiacumicin B inhibits the RNA polymerase (RNAP) by interaction with the “switch region” which stops RNA synthesis killing then bacteria. The discovery of such a new target is a rare and important event, as no cross-resistance with any other antibacterial agents is possible. The structure of this “switch region” is conserved all across bacterial species but is different from the one of superior animals, allowing selectively. In March 2013 the first nosocomial infection at Clostridium difficile resistant to classical antibiotics occurred in France; Around forty people were infected in a hospital in Marseille and three of them died. Tuberculosis is another infection that could be treated by tiacumicin B, and since its target does not overlap the rifamycins target on RNAP, no cross-resistance has been observed which is of premium importance since resistances have emerged.
Some tiacumicin B analogues were obtained through fermentation of unnatural precursors and by engineered gene-disrupted mutants of producer strains, approaches that led to limited structural modifications. Only about 40 of these analogues are known to date, some having nonetheless interesting activity on S. aureus and Enterococcus spp.. Considering the great medicinal potential of this new lead compound, the synthesis of a greater number of tiacumicin B analogues would be very valuable. This would widen and make more reliable structure-activity relationship (SAR) studies and would allow exploiting the precious new RNAP “switch region” target. However, getting deeper structural modifications definitely imposes the use of chemical synthesis. In this context, the best strategy consists in achieving the total synthesis of the natural product itself prior to the synthesis of analogues in order to pave a reliable pathway toward them. This is the first goal of the SynTia project that will call for a second project dedicated to the synthesis of analogues. Since neither the total synthesis of tiacumicin B nor even studies on this have been reported to date, the SynTia project will lead to the first total synthesis of tiacumicin B which constitutes a considerable and ambitious challenge. The intriguing architecture of natural products has always been regarded by organic chemists as a powerful source of inspiration stimulating continually the development of new strategies and methods of organic synthesis. The total synthesis of tiacumicin B corresponds to challenging and specific points calling for innovative solutions and new strategies for a straightforward, reliable, and elegant approach while using a sustainable and greener chemistry. Among other, the C12-C15 dienic motif has attracted our attention. Alkenes are very frequent structural motives but the control of their geometry remains a challenging task. We imagined building the C12-C15 dienic motif of tiacumicin B using a strategy based on the still under-explored albeit potential-rich, palladium-catalyzed cross-coupling of 1,1-dichloro-1-alkenes. Another structural particularity of tiacumicin B is that its polyketidic aglycone core is bonded to two sugars (D-noviose and D-rhamnose) through two 1,2-cis glycosidic bonds. The synthesis of such anomers remains a major carbohydrate chemistry challenge. Therefore, for the best chances of success, the Syntia project consortium gathers the complementary skills of recognized specialists of total synthesis and of glycochemistry featuring thus a rare and very promising association.