title: Chemical and functional properties of metal chelators that mobilize copper to elicit fungal killing of Cryptococcus neoformans.
abstract: A panel of iron (Fe) and copper (Cu) chelators was screened for growth inhibitory activity against the fungal pathogen Cryptococcus neoformans. Select bidentate metal-binding ligands containing mixed O,S or O,N donor atoms were identified as agents that induce cell killing in a Cu-dependent manner. Conversely, structurally similar ligands with O,O donor atoms did not inhibit C. neoformans growth regardless of Cu status. Studies of Cu(ii) and Cu(i) binding affinity, lipophilicity, and growth recovery assays of Cu-import deficient cells identified lipophilicity of thermodynamically stable CuIIL2complexes as the best predictor of antifungal activity. These same complexes induce cellular hyperaccumulation of Zn and Fe in addition to Cu. The results described here present the utility of appropriate metal-binding ligands as potential antifungal agents that manipulate cellular metal balance as an antimicrobial strategy.
authors.affiliation: Department of Chemistry, Duke University, French Family Science Center, 124 Science Drive, 22708, Durham, NC, USA. katherine.franz@duke.edu.
authors.forename: Marian E
authors.initials: ME
authors.lastname: Helsel
authors.affiliation: Department of Chemistry, Duke University, French Family Science Center, 124 Science Drive, 22708, Durham, NC, USA. katherine.franz@duke.edu.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: White
authors.affiliation: Department of Chemistry, Duke University, French Family Science Center, 124 Science Drive, 22708, Durham, NC, USA. katherine.franz@duke.edu.
authors.forename: Sayyeda Zeenat A
authors.initials: SZ
authors.lastname: Razvi
authors.affiliation: Department of Chemistry, Duke University, French Family Science Center, 124 Science Drive, 22708, Durham, NC, USA. katherine.franz@duke.edu.
authors.forename: Bruno
authors.initials: B
authors.lastname: Alies
authors.affiliation: Department of Chemistry, Duke University, French Family Science Center, 124 Science Drive, 22708, Durham, NC, USA. katherine.franz@duke.edu.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Franz
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D003455:Cryptococcus neoformans / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure
chemical_list: D000935:Antifungal Agents; D002614:Chelating Agents; D003300:Copper