Signaling cascades as drug targets in model and pathogenic fungi.

Published

Journal Article (Review)

Microbes evolved to produce natural products that inhibit growth of competing soil microorganisms. In many cases these compounds act on fungi, which are eukaryotes with conserved gene sequences closely related to metazoans, including humans. The calcineurin inhibitors cyclosporin A and FK-506, the Tor inhibitor rapamycin, and the Hsp90 inhibitor geldanamycin, all act via targets conserved from yeast to humans. This allows the use of genetically tractable fungi as models to elucidate how these drugs and their targets function in yeast and human cells. These inhibitors also enable studies aimed at harnessing their intrinsic antimicrobial activities to develop novel antifungal therapies. Extensive studies have revealed a globally conserved role for the Tor protein in regulating growth and proliferation in response to nutrients, and targeting its essential functions results in robust antifungal action. Similarly, a conserved and essential role for calcineurin in fungal virulence has been established and could be targeted by inhibitors for therapeutic uses in a variety of clinical settings. Finally, the discovery that inhibitors of calcineurin or Hsp90 result in dramatic synergism with either azoles or glucan synthase inhibitors (candins) provides another therapeutic vantage point. Taken together, these fungal targets and their inhibitors provide a robust platform from which to develop novel antimicrobial therapies.

Full Text

Duke Authors

Cited Authors

  • Bastidas, RJ; Reedy, JL; Morales-Johansson, H; Heitman, J; Cardenas, ME

Published Date

  • August 2008

Published In

Volume / Issue

  • 9 / 8

Start / End Page

  • 856 - 864

PubMed ID

  • 18666033

Pubmed Central ID

  • 18666033

Electronic International Standard Serial Number (EISSN)

  • 2040-3429

International Standard Serial Number (ISSN)

  • 1472-4472

Language

  • eng