Efflux-mediated antifungal drug resistance.
Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.
Cannon
Richard D
RD
Department of Oral Sciences, School of Dentistry, University of Otago, P.O. Box 647, Dunedin 9054, New Zealand. richard.cannon@otago.ac.nz
Lamping
Erwin
E
Holmes
Ann R
AR
Niimi
Kyoko
K
Baret
Philippe V
PV
Keniya
Mikhail V
MV
Tanabe
Koichi
K
Niimi
Masakazu
M
Goffeau
Andre
A
Monk
Brian C
BC
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000935:Antifungal Agents / Q000378:metabolism* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000502:physiology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005658:Fungi / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009181:Mycoses / Q000175:diagnosis / Q000188:drug therapy / Q000382:microbiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D014157:Transcription Factors