Enniatin has a new function as an inhibitor of Pdr5p, one of the ABC transporters in Saccharomyces cerevisiae

Biochem Biophys Res Commun. 2005 Mar 25;328(4):1119-25. doi: 10.1016/j.bbrc.2005.01.075.

Abstract

Pdr5p is one of the major multidrug efflux pumps whose overexpression confers multidrug resistance (MDR) in Saccharomyces cerevisiae. By using our original assay system, a fungal strain producing inhibitors for Pdr5p was obtained and classified as Fusarium sp. Y-53. The purified inhibitors were identified as ionophore antibiotics, enniatin B, B1, and D, respectively. A non-toxic concentration of each enniatin (5 microg/ml, approximately 7.8 microM) strongly inhibited a Pdr5p-mediated efflux of cycloheximide or cerulenin in Pdr5p-overexpressing cells. The enniatins accumulated a fluorescent dye rhodamine 123, a substrate of Pdr5p, into yeast cells. The mode of Pdr5p inhibition of enniatin was competitive against FK506, and its inhibitory activity was more potent with less toxicity than that of FK506. The enniatins showed similar inhibitory profile as FK506 against S1360 mutants (S1360A and S1360F) of Pdr5p. The enniatins did not inhibit the function of Snq2p, a homologue of Pdr5p. Thus, it was found that enniatins are potent and specific inhibitors for Pdr5p, with less toxicities than that of FK506.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / drug effects
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / drug effects
  • ATP-Binding Cassette Transporters / metabolism*
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology
  • Cell Survival / drug effects
  • Depsipeptides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple, Bacterial / drug effects
  • Drug Resistance, Multiple, Bacterial / physiology*
  • Gene Expression Regulation, Bacterial / drug effects
  • Metabolic Clearance Rate
  • Saccharomyces cerevisiae / classification
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Species Specificity

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP-Binding Cassette Transporters
  • Anti-Bacterial Agents
  • Depsipeptides
  • PDR5 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • enniatins