title: Signaling cascades as drug targets in model and pathogenic fungi.
abstract: 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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Research Drive, Box 3546, Durham, NC 27710, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bastidas
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Reedy
authors.forename: Helena
authors.initials: H
authors.lastname: Morales-Johansson
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.forename: Maria E
authors.initials: ME
authors.lastname: Cardenas
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016503:Drug Delivery Systems; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009181:Mycoses / Q000188:drug therapy* / Q000382:microbiology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D018841:HSP90 Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D017346:Protein Serine-Threonine Kinases; C500749:target of rapamycin protein, S cerevisiae; D019703:Calcineurin