Efflux-Mediated Antifungal Drug Resistance

Cannon, Richard D.; Lamping, Erwin; Holmes, Ann R.; Niimi, Kyoko; Baret, Philippe V.; Keniya, Mikhail V.; Tanabe, Koichi; Niimi, Masakazu; Goffeau, Andre; Monk, Brian C.

doi:10.1128/cmr.00051-08

Cited by 608Antifungal resistance and susceptibilityDrug Transport and Resistance MechanismsFungal and yeast genetics research

Efflux-Mediated Antifungal Drug Resistance

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Cannon, Richard D., Lamping, Erwin, Holmes, Ann R., Niimi, Kyoko, Baret, Philippe V., Keniya, Mikhail V., Tanabe, Koichi, Niimi, Masakazu +2 more·2009·Clinical Microbiology Reviews

DOI 10.1128/cmr.00051-08PMC PMC2668233

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Abstract

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.

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Efflux-mediated resistance mechanisms are not involved in adaptive resistance to echinocandins or polyenes, as they are poor pump substrates.
“In contrast, efflux-mediated resistance mechanisms are not involved in adaptive resistance to echinocandins or polyenes, as they are poor pump substrates49.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [49]
A mechanism for decreasing intracellular azole concentration relies on upregulation of efflux pumps, including Cdr ABC pumps encoded by CDR1/CDR2 and an MFS pump encoded by MDR1 that is specific for fluconazole.
“A responsible mechanism for decreasing the intracellular concentration of azole relies on an upregulation of two principal families of efflux pumps (reviewed in [96]). These transporters differ in the source of energy used to pump out the drug and in the specificity of the azole molecule. The Cdr pumps belong to the superfamily of ATP-binding cassette (ABC) transporters and are able to extrude all”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [96]

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Authors: Cannon, R. D., Lamping, E., Holmes, A. R., Niimi, K., Baret, P. V., Keniya, M. V., Tanabe, K., Niimi, M., Goffeau, A., & Monk, B. C.
Affiliations: University of Otago (NZ)
UCLouvain (BE)
National Institute of Infectious Diseases (JP)
Université Catholique de Louvain, Louvain-la-Neuve, Belgium
ORCID: Cannon, Richard D.
Lamping, Erwin
Holmes, Ann R.
Baret, Philippe V.
Keniya, Mikhail V.
Tanabe, Koichi
Monk, Brian C.
Venue: Clinical Microbiology Reviews
Publisher: American Society for Microbiology
Published: 2009-04
Volume: 22
Issue: 2
Pages: 291-321
ISSN: 0893-8512 (ISSN-L)
1098-6618
DOI: 10.1128/cmr.00051-08
PMC: PMC2668233
OpenAlex: W2163758697
Cited by: 608
References: 399
Citations by year: 2026: 28 · 2025: 30 · 2024: 33 · 2023: 35 · 2022: 32 · 2021: 44 · 2020: 42 · 2019: 34 · 2018: 28 · 2017: 40 · 2016: 35 · 2015: 36 · 2014: 51 · 2013: 42 · 2012: 32
FWCI: 3.56
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Clinical Microbiology Reviews (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DIAL (Catholic University of Leuven) (submittedVersion)
Funders: National Institute of Dental and Craniofacial Research (R01DE016885)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: azole resistance, ABC transporters, major facilitator superfamily, pleiotropic drug resistance, echinocandins, fungal stress response, efflux pump inhibition, invasive fungal infections, antifungal drug development
MeSH terms: Antifungal Agents, DNA-Binding Proteins, Fungal Proteins, Fungi, Humans, Membrane Proteins, Mycoses, Transcription Factors, ATP-Binding Cassette Transporters, Drug Resistance, Fungal, Membrane Transport Proteins

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Efflux-Mediated Antifungal Drug Resistance

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