Abstract

Equisetin, Reutericyclin and Streptolodygin as Natural Product Lead Structures for Novel Antibiotic Libraries

Mark Moloney, Professor of Chemistry, University of Oxford

The discovery of new antibiotics has become urgent as a result of the emergence of resistance and new pathogenic bacterial strains. However, this need has coincided with unprecedented lowering of levels of productivity in the drug discovery process and consequent reduced investment from large pharma. New strategies for antibacterial drug discovery are required, and a renewed understanding of the value of a natural products’ guided approach has emerged. Our focus has been on the use of antibacterial natural products containing tetramate core structures, and using equisetin and reutericyclin as inspiration, we have developed novel chemistry that uses suitable serine, threonine and cysteine-derived oxazolidine templates for highly chemo- and diasteroselective ring closure reactions leading to tetramic acid derivatives. Although simple unsubstituted pyrrolidines and tetramates appear to be intrinsically devoid of activity, application of these templates for fragment-based synthesis, has permitted access to several compound series which possess high levels of antibacterial activity, SAR analysis has permitted some optimization of the initial activity and MOA and other pharmacokinetic data been obtained. This lecture will illustrate the potential of natural products to guide antibacterial drug discovery, the role of synthetic organic chemistry in the construction of libraries which mimic these natural products, and suggest a possible way forward for more efficient drug discovery strategies.