title: Zinc pyrithione inhibits yeast growth through copper influx and inactivation of iron-sulfur proteins.
abstract: Zinc pyrithione (ZPT) is an antimicrobial material with widespread use in antidandruff shampoos and antifouling paints. Despite decades of commercial use, there is little understanding of its antimicrobial mechanism of action. We used a combination of genome-wide approaches (yeast deletion mutants and microarrays) and traditional methods (gene constructs and atomic emission) to characterize the activity of ZPT against a model yeast, Saccharomyces cerevisiae. ZPT acts through an increase in cellular copper levels that leads to loss of activity of iron-sulfur cluster-containing proteins. ZPT was also found to mediate growth inhibition through an increase in copper in the scalp fungus Malassezia globosa. A model is presented in which pyrithione acts as a copper ionophore, enabling copper to enter cells and distribute across intracellular membranes. This is the first report of a metal-ligand complex that inhibits fungal growth by increasing the cellular level of a different metal.
authors.affiliation: Procter & Gamble Co, Miami Valley Innovation Center, Cincinnati, Ohio 45253-8707, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Reeder
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: R Scott
authors.initials: RS
authors.lastname: Youngquist
authors.forename: Jared
authors.initials: J
authors.lastname: Wallace
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: Kenton D
authors.initials: KD
authors.lastname: Juhlin
authors.forename: James R
authors.initials: JR
authors.lastname: Schwartz
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Grant
authors.forename: Angela
authors.initials: A
authors.lastname: Fieno
authors.forename: Suzanne
authors.initials: S
authors.lastname: Nemeth
authors.forename: Tim
authors.initials: T
authors.lastname: Reichling
authors.forename: Jay P
authors.initials: JP
authors.lastname: Tiesman
authors.forename: Tim
authors.initials: T
authors.lastname: Mills
authors.forename: Mark
authors.initials: M
authors.lastname: Steinke
authors.forename: Shuo L
authors.initials: SL
authors.lastname: Wang
authors.forename: Charles W
authors.initials: CW
authors.lastname: Saunders
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008290:Malassezia / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D020411:Oligonucleotide Array Sequence Analysis; D009942:Organometallic Compounds / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D017384:Sequence Deletion
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D007506:Iron-Sulfur Proteins; D009942:Organometallic Compounds; D011725:Pyridines; D003300:Copper; C010423:pyrithione zinc