title: Targeting efflux pumps to overcome antifungal drug resistance.
abstract: Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.
authors.affiliation: Sir John Walsh Research Institute, University of Otago Faculty of Dentistry, PO Box 647, Dunedin 9054, New Zealand.
authors.forename: Ann R
authors.initials: AR
authors.lastname: Holmes
authors.affiliation: Department of Biochemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand.|Walter & Eliza Hall Institute of Medical Research Biotechnology Center, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Tony S
authors.initials: TS
authors.lastname: Cardno
authors.affiliation: New Mexico Center for Molecular Discovery, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: J Jacob
authors.initials: JJ
authors.lastname: Strouse
authors.affiliation: New Mexico Center for Molecular Discovery, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Irena
authors.initials: I
authors.lastname: Ivnitski-Steele
authors.affiliation: Sir John Walsh Research Institute, University of Otago Faculty of Dentistry, PO Box 647, Dunedin 9054, New Zealand.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Keniya
authors.affiliation: Walter & Eliza Hall Institute of Medical Research Biotechnology Center, Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Kurt
authors.initials: K
authors.lastname: Lackovic
authors.affiliation: Sir John Walsh Research Institute, University of Otago Faculty of Dentistry, PO Box 647, Dunedin 9054, New Zealand.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Monk
authors.affiliation: New Mexico Center for Molecular Discovery, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.affiliation: Sir John Walsh Research Institute, University of Otago Faculty of Dentistry, PO Box 647, Dunedin 9054, New Zealand.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cannon
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D005658:Fungi / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D026901:Membrane Transport Proteins
keywords: ABC and MFS transporters; antifungal drug resistance; azole; chemosensitization; heterologous expression; high-throughput screen