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Review
. 2018 Sep 1;4(3):105.
doi: 10.3390/jof4030105.

Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata

Kelley R Healey  1 , David S Perlin  2
Affiliations
Review

Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata

Kelley R Healey et al. J Fungi (Basel). .

Abstract

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures. prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable "genetic escape". Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata is highlighted.

Keywords: Candida glabrata; FKS; MSH2; azole; drug resistance; echinocandin; tolerance.

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Conflict of interest statement

D.S.P. receives funding from US National Institutes of Health and contracts from the CDC, Astellas, Scynexis, Cidara and Amplyx. He serves on advisory boards for Astellas, Cidara, Amplyx, Scynexis, and Matinas. In addition, D.S.P. has an issued US patent concerning echinocandin resistance. K.R.H. declares no competing financial interests. The authors alone are responsible for the content and writing of the paper.

Figures

Figure 1
Figure 1
Phases of in vitro cell killing and adaptation with echinocandins and Candida glabrata. Cells (1×107) of C. glabrata ATCC 2001 were grown in RPMI medium containing caspofungin at the indicated concentrations for 20 h. Dilutions were then plated onto drug free agar-containing plates to determine surviving cell counts. Shown is the average of 4 independent experiments ± standard deviations. The minimum inhibitory concentration (MIC) is indicated for reference.
Figure 2
Figure 2
Evolution of echinocandin resistance. Cellular factors that influence the ability of yeast to adapt to echinocandin drug pressure are represented in a multistep model of resistance. Steps include initial cellular stress, drug adaptation, and genetic escape (FKS mutation). The clinical breakpoint (CBP) of a species is the MIC measured prior to the formation of FKS escape mutants.
Figure 3
Figure 3
Echinocandin, azole, and polyene resistant colony frequencies of C. glabrata mismatch repair deletion strains. Strains were selected agar plates containing 1 µg/mL of caspofungin (CSF), 256 µg/mL of fluconazole (FLC), or 2 µg/mL of amphotericin B (AmpB) (panels left to right) (all concentrations 8-16x the corresponding MIC). Dilutions were plated onto drug-free media to determine exact CFU counts. Frequencies were calculated as the number of colonies on the drug plate divided by the total CFU plated. Frequency averages were calculated from at least three independent selections. * p < 0.05 and ** p < 0.01 (student’s t-test; two-tailed).
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