title: The marine sponge-derived polyketide endoperoxide plakortide F acid mediates its antifungal activity by interfering with calcium homeostasis.
abstract: Plakortide F acid (PFA), a marine-derived polyketide endoperoxide, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. PFA elicited a transcriptome response indicative of a Ca(2+) imbalance, affecting the expression of genes known to be responsive to altered cellular calcium levels. Several additional lines of evidence obtained supported a role for Ca(2+) in PFA's activity. First, mutants lacking calcineurin and various Ca(2+) transporters, including pumps (Pmr1 and Pmc1) and channels (Cch1 and Mid1), showed increased sensitivity to PFA. In addition, the calcineurin inhibitors FK506 and cyclosporine strongly enhanced PFA activity in wild-type cells. Furthermore, PFA activated the transcription of a lacZ reporter gene driven by the calcineurin-dependent response element. Finally, elemental analysis indicated a significant increase in intracellular calcium levels in PFA-treated cells. Collectively, our results demonstrate that PFA mediates its antifungal activity by perturbing Ca(2+) homeostasis, thus representing a potentially novel mechanism distinct from that of currently used antifungal agents.
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Qin
authors.initials: Q
authors.lastname: Feng
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Jacob
authors.forename: Bharathi
authors.initials: B
authors.lastname: Avula
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Mask
authors.forename: Scott R
authors.initials: SR
authors.lastname: Baerson
authors.forename: Siddharth K
authors.initials: SK
authors.lastname: Tripathi
authors.forename: Rabab
authors.initials: R
authors.lastname: Mohammed
authors.forename: Mark T
authors.initials: MT
authors.lastname: Hamann
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Alice M
authors.initials: AM
authors.lastname: Clark
authors.forename: Ameeta K
authors.initials: AK
authors.lastname: Agarwal
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D004146:Dioxanes; C102699:plakortide F; D002118:Calcium