title: Cerulenin analogues as inhibitors of efflux pumps in drug-resistant Candida albicans.
abstract: Overexpression of the ABC transporters Cdr1 and Cdr2 or the major facilitator Mdr1 causes multidrug resistance in the human fungal pathogen Candida albicans. The fatty acid synthesis inhibitor cerulenin and the structurally unrelated Golgi transport inhibitor brefeldin A are substrates for both types of efflux pumps in Candida albicans. In an effort to overcome efflux pump-mediated drug resistance in Candida albicans, cerulenin analogues were generated using a variety of synthesis pathways. The so obtained cerulenin derivatives were tested on multidrug-resistant Candida albicans isolates which constitutively overexpress either Mdr1 or Cdr1 and Cdr2. Some of these compounds were found to decrease Mdr1-mediated resistance to brefeldin A up to eightfold compared to the control.
authors.affiliation: Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Würzburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Diwischek
authors.forename: Joachim
authors.initials: J
authors.lastname: Morschhäuser
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects*; D002569:Cerulenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D026901:Membrane Transport Proteins
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D002569:Cerulenin; D020126:Brefeldin A