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Lactate Like Fluconazole Reduces Ergosterol Content in the Plasma Membrane and Synergistically Kills Candida albicans.

ABSTRACT: Candida albicans is an opportunistic pathogen that induces vulvovaginal candidiasis (VVC), among other diseases. In the vaginal environment, the source of carbon for C. albicans can be either lactic acid or its dissociated form, lactate. It has been shown that lactate, similar to the popular antifungal drug fluconazole (FLC), reduces the expression of the ERG11 gene and hence the amount of ergosterol in the plasma membrane. The Cdr1 transporter that effluxes xenobiotics from C. albicans cells, including FLC, is delocalized from the plasma membrane to a vacuole under the influence of lactate. Despite the overexpression of the CDR1 gene and the increased activity of Cdr1p, C. albicans is fourfold more sensitive to FLC in the presence of lactate than when glucose is the source of carbon. We propose synergistic effects of lactate and FLC in that they block Cdr1 activity by delocalization due to changes in the ergosterol content of the plasma membrane.

SUBMITTER: Suchodolski J

PROVIDER: S-EPMC8156871 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Lactate Like Fluconazole Reduces Ergosterol Content in the Plasma Membrane and Synergistically Kills Candida albicans.

Suchodolski Jakub J Muraszko Jakub J Bernat Przemysław P Krasowska Anna A

International journal of molecular sciences 20210514 10

Candida albicans is an opportunistic pathogen that induces vulvovaginal candidiasis (VVC), among other diseases. In the vaginal environment, the source of carbon for C. albicans can be either lactic acid or its dissociated form, lactate. It has been shown that lactate, similar to the popular antifungal drug fluconazole (FLC), reduces the expression of the ERG11 gene and hence the amount of ergosterol in the plasma membrane. The Cdr1 transporter that effluxes xenobiotics from ...[more]

PMID: 34069257

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Project description:Background and purposeThe frequency of opportunistic fungal infections in immunocompromised patients, especially by Candida species, has sharply increased in the last few decades. The objective of this study was to analyse the ergosterol content and gene expression profiling of clinical isolates of fluconazole-resistant Candida albicans.Materials and methodsSixty clinical samples were identified and collected from immunocompromised patients, namely recurrent oral, vaginal, and cutaneous candidiasis, during 2015-16. Antifungal susceptibility testing of fluconazole against clinical Candida species was performed according to Clinical and Laboratory Standards Institute guidelines. Ergosterol content and gene expression profiling of sterol 14α-demethylase (ERG11) gene in fluconazole-susceptible and -resistant C. albicans were investigated.ResultsThe specimens consisted of C. albicans (46.67%), Candida krusei (41.67%), and Candida tropicalis (11.67%). All the isolates were resistant to fluconazole. No significant reduction was noted in total cellular ergosterol content in comparison with untreated controls in terms of fluconazole-resistant C. albicans. The expressionlevel of ERG11 gene was down-regulated in fluconazole-susceptible C. albicans. Eventually, the expression pattern of ERG11 gene revealed no significant changes in fluconazole-resistant isolates compared to untreated controls. The results revealed no significant differences between fluconazole-susceptible and -resistant C. albicans sequences by comparison with ERG11 reference sequence.ConclusionOur findings provide an insight into the mechanism of fluconazole resistance in C. albicans. The mechanisms proposed for clinical isolates of fluconazole-resistant C. albicans are alteration in sterol biosynthesis, analysis of expression level of ERG11 gene, and analysis of gene sequences. Nonetheless, further studies are imperative to find molecular mechanisms that could be targeted to control fluconazole resistance.

Project description:Candidiasis is reported to be the most common fungal infection in the critical care setting. The causative agent of this infection is a commensal pathogen belonging to the genus Candida, the most common species of which is Candida albicans. The ergosterol pathway in yeast is a common target by many antifungal agents, as ergosterol is an essential component of the cell membrane. The current antifungal agent of choice for the treatment of candidiasis is fluconazole, which is classified under the azole antifungals. In recent years, the significant increase of fluconazole-resistant C. albicans in clinical samples has revealed the need for a search for other possible drug targets. In this study, we constructed a mathematical model of the ergosterol pathway of C. albicans using ordinary differential equations with mass action kinetics. From the model simulations, we found the following results: (i) a partial inhibition of the sterol-methyltransferase enzyme yields a fair amount of fluconazole resistance; (ii) the overexpression of the ERG6 gene, which leads to an increased sterol-methyltransferase enzyme, is a good target of antifungals as an adjunct to fluconazole; (iii) a partial inhibition of lanosterol yields a fair amount of fluconazole resistance; (iv) the C5-desaturase enzyme is not a good target of antifungals as an adjunct to fluconazole; (v) the C14α-demethylase enzyme is confirmed to be a good target of fluconazole; and (vi) the dose-dependent effect of fluconazole is confirmed. This study hopes to aid experimenters in narrowing down possible drug targets prior to costly and time-consuming experiments and serve as a cross-validation tool for experimental data. IMPORTANCE Candidiasis is reported to be the most common fungal infection in the critical care setting, and it is caused by a commensal pathogen belonging to the genus Candida, the most common species of which is Candida albicans. The current antifungal agent of choice for the treatment of candidiasis is fluconazole, which is classified under the azole antifungals. There has been a significant increase in fluconazole-resistant C. albicans in recent years, which has revealed the need for a search for other possible drug targets. We constructed a mathematical model of the ergosterol pathway in C. albicans using ordinary differential equations with mass action kinetics. In our simulations, we found that by increasing the amount of the sterol-methyltransferase enzyme, C. albicans becomes more susceptible to fluconazole. This study hopes to aid experimenters in narrowing down the possible drug targets prior to costly and time-consuming experiments and to serve as a cross-validation tool for experimental data.

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Lactate Like Fluconazole Reduces Ergosterol Content in the Plasma Membrane and Synergistically Kills Candida albicans.

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Lactate Like Fluconazole Reduces Ergosterol Content in the Plasma Membrane and Synergistically Kills <i>Candida albicans</i>.

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