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Antimicrobial Agents and Chemotherapy, October 1998, p. 2694-2699, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Translation Elongation Factor 2 Is Part of the Target for a New Family of Antifungals

Laura Capa, Alfonso Mendoza, José L. Lavandera, Federico Gómez de las Heras, and José F. García-Bustos*

Research Department, Glaxo Wellcome, S.A., 28760 Tres Cantos, Spain

Received 1 May 1998/Returned for modification 29 June 1998/Accepted 15 July 1998

Translation elongation factor 2 (EF2), which in Saccharomyces cerevisiae is expressed from the EFT1 and EFT2 genes, has been found to be targeted by a new family of highly specific antifungal compounds derived from the natural product sordarin. Two complementation groups of mutants resistant to the semisynthetic sordarin derivative GM193663 were found. The major one (21 members) consisted of isolates with mutations on EFT2. The minor one (four isolates) is currently being characterized but it is already known that resistance in this group is not due to mutations on EFT1, pointing to the complex structure of the functional target for these compounds. Mutations on EF2 clustered, forming a possible drug binding pocket on a three-dimensional model of EF2, and mutant cell extracts lost the capacity to bind to the inhibitors. This new family of antifungals holds the promise to be a much needed and potent addition to current antimicrobial treatments, as well as a useful tool for dissection of the elongation process in ribosomal protein synthesis.

* Corresponding author. Mailing address: Research Department, Glaxo Wellcome, S.A., Severo Ochoa 2, 28760 Tres Cantos, Spain. Phone: 34-91-807-0606. Fax: 34-91-807-0550. E-mail: jfg32652{at}glaxowellcome.co.uk.

Antimicrobial Agents and Chemotherapy, October 1998, p. 2694-2699, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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