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Clinical Microbiology Reviews, April 2009, p. 291-321, Vol. 22, No. 2
0893-8512/09/$08.00+0     doi:10.1128/CMR.00051-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Efflux-Mediated Antifungal Drug Resistance{dagger}

Richard D. Cannon,1* Erwin Lamping,1 Ann R. Holmes,1 Kyoko Niimi,1 Philippe V. Baret,2 Mikhail V. Keniya,1 Koichi Tanabe,3 Masakazu Niimi,3 Andre Goffeau,2 and Brian C. Monk1 Author Bios

Department of Oral Sciences, School of Dentistry, University of Otago, Dunedin, New Zealand,1 Université Catholique de Louvain, Louvain-la-Neuve, Belgium,2 Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan3

Summary: 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.

* Corresponding author. Mailing address: Department of Oral Sciences, School of Dentistry, University of Otago, P.O. Box 647, Dunedin 9054, New Zealand. Phone: 64 3 479 7081. Fax: 64 3 479 7078. E-mail: richard.cannon{at}otago.ac.nz

{dagger} Supplemental material for this article may be found at http://cmr.asm.org/.

Clinical Microbiology Reviews, April 2009, p. 291-321, Vol. 22, No. 2
0893-8512/09/$08.00+0     doi:10.1128/CMR.00051-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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