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PMID: 19366916 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Efflux-mediated antifungal drug resistance.

Clinical microbiology reviews ·Vol. 22 ·No. 2 ·2009-04-00 ·Pages 291-321, Table of Contents

Cannon RD, Lamping E, Holmes AR, Niimi K, Baret PV, Keniya MV, Tanabe K, Niimi M, Goffeau A, Monk BC

Abstract

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.

MeSH Terms
ATP-Binding Cassette Transporters/genetics,metabolism Antifungal Agents/metabolism,pharmacology DNA-Binding Proteins/genetics,metabolism Drug Resistance, Fungal/physiology Fungal Proteins/genetics,metabolism Fungi/drug effects,genetics,metabolism Humans Membrane Proteins/genetics,metabolism Membrane Transport Proteins/metabolism Mycoses/diagnosis,drug therapy,microbiology Transcription Factors/genetics,metabolism
Chemicals
ATP-Binding Cassette Transporters Antifungal Agents DNA-Binding Proteins Fungal Proteins Membrane Proteins Membrane Transport Proteins Transcription Factors
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Cannon Richard D
Department of Oral Sciences, School of Dentistry, University of Otago, P.O. Box 647, Dunedin 9054, New Zealand. [email protected]
Lamping Erwin
Holmes Ann R
Niimi Kyoko
Baret Philippe V
Keniya Mikhail V
Tanabe Koichi
Niimi Masakazu
Goffeau Andre
Monk Brian C
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Article Info
Journal
Clinical microbiology reviews
Abbr.
Clin Microbiol Rev
ISSN
1098-6618
DOI
10.1128/CMR.00051-08
Email
[email protected]
Published
2009-04-00
Pages
291-321, Table of Contents
Language
English
Region
United States
NLM ID
8807282
PMCID
PMC2668233
Subset
IM
Grants
NIDCR NIH HHS · R01 DE016885 · United States
NIDCR NIH HHS · R01DE016885-01-RDC · United States
External Links
PubMed source DOI: 10.1128/CMR.00051-08 PMC Full Text View journal details
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