Candida albicans Clinical Isolates from a Southwest Brazilian Tertiary Hospital Exhibit MFS-mediated Azole Resistance Profile

Pinto, Ana Carolina Cartagenes; Rocha, Débora Afonso Silva; Moraes, Daniel Clemente de; Junqueira, Maria Luiza; Ferreira‐Pereira, Antônio

doi:10.1590/0001-3765201920180654

Cited by 6 publications

(6 citation statements)

References 26 publications

(13 reference statements)

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“…Due to the increasing resistance of Candida species associated with invasive infections and the potential of targeting sphingolipids, the present study aimed to test two inhibitors of sphingolipid synthesis, aureobasidin A and myriocin. Both drugs were evaluated against different Candida clinical isolates, including some that were described as strains that overexpress transmembrane transporters (ABC and MFS) related to multidrug resistance phenotype [ 24 , 25 ]. Aureobasidin A and myriocin inhibit inositolphosphorylceramide (IPC) synthase and glucosylceramide (GlcCer) synthase, respectively, which are two key enzymes for the synthesis of the most important sphingolipids found in fungi such as IPC and GlcCer.…”

Section: Introductionmentioning

confidence: 99%

Sphingolipid Inhibitors as an Alternative to Treat Candidiasis Caused by Fluconazole-Resistant Strains

et al. 2021

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Candida species are fungal pathogens known to cause a wide spectrum of diseases, and Candida albicans and Candida glabrata are the most common associated with invasive infections. A concerning aspect of invasive candidiasis is the emergence of resistant isolates, especially those highly resistant to fluconazole, the first choice of treatment for these infections. Fungal sphingolipids have been considered a potential target for new therapeutic approaches and some inhibitors have already been tested against pathogenic fungi. The present study therefore aimed to evaluate the action of two sphingolipid synthesis inhibitors, aureobasidin A and myriocin, against different C. albicans and C. glabrata strains, including clinical isolates resistant to fluconazole. Susceptibility tests of aureobasidin A and myriocin were performed using CLSI protocols, and their interaction with fluconazole was evaluated by a checkerboard protocol. All Candida strains tested were sensitive to both inhibitors. Regarding the evaluation of drug interaction, both aureobasidin A and myriocin were synergic with fluconazole, demonstrating that sphingolipid synthesis inhibition could enhance the effect of fluconazole. Thus, these results suggest that sphingolipid inhibitors in conjunction with fluconazole could be useful for treating candidiasis cases, especially those caused by fluconazole resistant isolates.

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Section: Introductionmentioning

confidence: 99%

Sphingolipid Inhibitors as an Alternative to Treat Candidiasis Caused by Fluconazole-Resistant Strains

et al. 2021

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“…A clinical isolate of C. albicans , overexpressing CaMdr1 and CaCdr1 (strain 1114) [ 34 ] and the CgCdr1-overexpressing C. glabrata clinical isolate 109 [ 35 , 36 ], both obtained from patients at the University Hospital of Universidade Federal de Juiz de Fora, Minas Gerais, were used. The strains were identified by MALDI-TOF mass spectroscopy [ 35 , 36 ].…”

Section: Methodsmentioning

confidence: 99%

“…The capacity of the most active extracts to cause cells to accumulate the fluorescent cell-associated substrate of Mdr1 and Cdr1, Nile Red [ 41 – 43 ], was monitored by flow cytometry. Briefly, resistant and sensitive yeasts grown to exponential phase in SDB were centrifuged, washed two times with distilled water and kept on ice for 2 h [ 34 ]. Then, cells were incubated in 96-well microtitre plates (1 × 10 6 cells /well) containing SDB in the absence or presence of different concentrations of the extracts dissolved in DMSO at 30 °C for 2 h with shaking at 200 rpm.…”

Section: Methodsmentioning

confidence: 99%

Extracts from Argentinian native plants reverse fluconazole resistance in Candida species by inhibiting the efflux transporters Mdr1 and Cdr1

Gil

Laiolo

Bayona-Pacheco

et al. 2022

BMC Complement Med Ther

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Background The development of multidrug resistance (MDR) associated with the overexpression of the efflux transporters Mdr1 and Cdr1 in Candida species impedes antifungal therapies. The urgent need for novel agents able to inhibit the function of both pumps, led us to evaluate this property in 137 extracts obtained from Argentinian plants. Methods The ability of the extracts to reverse efflux pump-mediated MDR was determined with an agar chemosensitization assay using fluconazole (FCZ) resistant Mdr1- and Cdr1-overexpressing clinical isolates of Candida albicans and Candida glabrata as well as Saccharomyces cerevisiae strains selectively expressing Mdr1 (AD/CaMDR1) or Cdr1 (AD/CaCDR1). The resistance-reversing activity of the most potent extracts was further confirmed using a Nile Red accumulation assay. Results Fifteen plant extracts overcame the FCZ resistance of Candida albicans 1114, which overexpresses CaMdr1 and CaCdr1, and AD/CaMDR1, with those from Acalypha communis and Solanum atriplicifolium being the most effective showing 4- to 16-fold reversal of resistance at concentrations ≥ 25 µg/mL. Both extracts, and to a lesser extent that from Pterocaulon alopecuroides, also restored FCZ sensitivity in CgCdr1-overexpressing C. glabrata 109 and in AD/CaCDR1 with fold reversal values ranging from 4 to 32 and therefore demonstrating a dual effect against Mdr1 and Cdr1. Both, A. communis and S. atriplicifolium extracts at concentrations ≥ 12.5 and ≥ 25 µg/mL, respectively, increased the intracellular Nile Red accumulation in all yeast strains overexpressing efflux pumps. Conclusions The non-toxic and highly active extracts from A. communis and S. atripicifolium, provide promising sources of compounds for potentiating the antifungal effect of FCZ by blocking the efflux function of Mdr1 and Cdr1 transporters.

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“…A clinical isolate of C. albicans, overexpressing CaMdr1 and CaCdr1 (strain 1114) [34] and the CgCdr1overexpressing C. glabrata clinical isolate 109 [35,36], were used. Minimum inhibitory concentration (MIC) values, determined with an agar dilution assay as described below, revealed that strain 1114 was 515-times more resistant to FCZ than the sensitive strain C. albicans ATCC 90028 (MIC FCZ = 500 and 0.97 µg/mL, respectively) [37], whereas strain 109 displayed 64-fold more resistance to FCZ than C. glabrata ATCC 2001 (MIC FCZ = 1,000 and 15.6 µg/mL, respectively) [37].…”

Section: Strains and Culture Conditionsmentioning

confidence: 99%

“…The capacity of the most active extracts to cause cells to accumulate the uorescent cell-associated substrate of Mdr1 and Cdr1, Nile Red [41][42][43], was monitored by ow cytometry. Brie y, resistant and sensitive yeasts grown to exponential phase in SDB were centrifuged, washed two times with distilled water and kept on ice for 2 h [34]. Then, cells were incubated in 96-well culture plates (1 x 10 6 cells /well) containing SDB in the absence or presence of different concentrations of the extracts dissolved in DMSO at 30°C for 2 h with shaking at 200 rpm.…”

Section: Nile Red Accumulation Assaymentioning

confidence: 99%

Extracts from Argentinian native plants reverse fluconazole resistance in Candida species by inhibiting the efflux transporters Mdr1 and Cdr1

Gil

Laiolo

Bayona-Pacheco³

et al. 2022

Preprint

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Background: The development of multidrug resistance (MDR) associated with the overexpression of the efflux transporters Mdr1 and Cdr1 in Candida species impedes antifungal therapies. The urgent need for novel agents able to inhibit the function of both pumps, led us to evaluate this property in 137 extracts obtained from Argentinian plants. Methods: The ability of the extracts to reverse efflux pump-mediated MDR was determined with an agar chemosensitization assay using fluconazole (FCZ) resistant Mdr1- and Cdr1-overexpressing clinical isolates of Candida albicans and Candida glabrata as well as Saccharomyces cerevisiae strains selectively expressing Mdr1 (AD/CaMDR1) or Cdr1 (AD/CaCDR1). The resistance-reversing activity of the most potent extracts was further confirmed using a Nile Red accumulation assay. Results: Fifteen plant extracts overcame the FCZ resistance of Candida albicans 1114, which overexpresses CaMdr1 and CaCdr1, and AD/CaMDR1, with those from Acalypha communis and Solanum atriplicifolium being the most effective showing 4- to 16-fold reversal of resistance at concentrations ≥ 25 µg/mL. Both extracts, and to a lesser extent that from Pterocaulon alopecuroides, also restored FCZ sensitivity in CgCdr1-overexpressing C. glabrata 109 and in AD/CaCDR1 with fold reversal values ranging from 4 to 32 and therefore demonstrating a dual effect against Mdr1 and Cdr1. Both, A. communis and S. atriplicifolium extracts at concentrations ≥ 12.5 and ≥ 25 µg/mL, respectively, increased the intracellular Nile Red accumulation in all yeast strains overexpressing efflux pumps. Conclusions: The non-toxic and highly active extracts from A. communis and S. atripicifolium, provide promising sources of compounds for potentiating the antifungal effect of FCZ by blocking the efflux function of Mdr1 and Cdr1 transporters.

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Candida albicans Clinical Isolates from a Southwest Brazilian Tertiary Hospital Exhibit MFS-mediated Azole Resistance Profile

Cited by 6 publications

References 26 publications

Sphingolipid Inhibitors as an Alternative to Treat Candidiasis Caused by Fluconazole-Resistant Strains

Sphingolipid Inhibitors as an Alternative to Treat Candidiasis Caused by Fluconazole-Resistant Strains

Extracts from Argentinian native plants reverse fluconazole resistance in Candida species by inhibiting the efflux transporters Mdr1 and Cdr1

Extracts from Argentinian native plants reverse fluconazole resistance in Candida species by inhibiting the efflux transporters Mdr1 and Cdr1

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