TRANSLATION ELONGATION-FACTOR-2 IS PART OF THE TARGET FOR A NEW FAMILY OF ANTIFUNGALS

Translation elongation factor 2 (EF2), which in Saccharomyces cerevisi ae is expressed from the EFT1 and EFT2 genes, has been found to he tar geted by a new family of highly specific antifungal compounds derived from the natural product sordarin, Two complementation groups of mutan ts resistant to the semisynthetic sordarin derivative GM193663 were fo und. The major one (21 members) consisted of isolates with mutations o n EFT2, The minor one (four isolates) is currently being characterized but it is already known that resistance in this group is not due to m utations on EFT1, pointing to the complex structure of the functional target for these compounds. Mutations on EF2 clustered, forming a poss ible drug binding Docket on a three-dimensional model of EF2, and muta nt cell extracts lost the capacity to bind to the inhibitors. This new ; family of antifungals holds the promise to be a much needed and pote nt addition to current antimicrobial treatments, as well as a useful t ool for dissection of the elongation process in ribosomal protein synt hesis.