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Review
. 2016 Aug;8(12):1485-501.
doi: 10.4155/fmc-2016-0050. Epub 2016 Jul 27.

Targeting efflux pumps to overcome antifungal drug resistance

Ann R Holmes  1 , Tony S Cardno  2   3   4 , J Jacob Strouse  5 , Irena Ivnitski-Steele  5 , Mikhail V Keniya  1 , Kurt Lackovic  3   4 , Brian C Monk  1 , Larry A Sklar  5 , Richard D Cannon  1
Affiliations
Review

Targeting efflux pumps to overcome antifungal drug resistance

Ann R Holmes et al. Future Med Chem. 2016 Aug.

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.

Keywords: ABC and MFS transporters; antifungal drug resistance; azole; chemosensitization; heterologous expression; high-throughput screen.

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Conflict of interest statement

Financial & competing interests disclosure

RD Cannon acknowledges funding from the NIH (R01-DE016855-01; R03-MH087406-1A1) and the Royal Society of New Zealand Marsden Fund (UOO1305). LA Sklar acknowledges funding from the NIH (U54 MH074425/MH086490). TS Cardno was funded by the Health Research Council of New Zealand's International Investment Opportunities Fund (IIOF 09_04). BC Monk was supported by the Health Research Council of New Zealand. AR Holmes was supported by the University of Otago. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Possible drug targets on fungal ABC efflux pumps.
NBD: Nucleotide-binding domain; TMD: Transmembrane domain.
<b>Figure 2.</b>
Figure 2.. Fungal efflux pumps identified through screens.
NR: Not reported.
<b>Figure 3.</b>
Figure 3.. Screening process using heterologous expression of fungal efflux pumps.
<b>Figure 4.</b>
Figure 4.. Whole-cell fluorescence-based fungal efflux pump assays for high-throughput screens.
HTS: High-throughput screen
See this image and copyright information in PMC

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