Magnesium deprivation affects cellular circuitry involved in drug resistance and virulence in Candida albicans

Objectives: Candida albicans has to struggle for the limited micronutrients present in the hostile host niche, including magnesium (Mg). The aim of this study was to examine the effect of Mg deprivation on drug resistance mechanisms and virulence traits of C. albicans. Methods: The drug susceptibility of C. albicans strain SC5314 was determined by broth microdilution and spot assay. Efflux pump activity was measured using the substrate rhodamine 6G. Membrane intactness was studied by propidium iodide influx, and ergosterol levels were determined by the alcoholic KOH method. Metabolic flexibility was examined by studying the activity of glyoxylate cycle enzymes. Virulence factors were assessed by yeast-to-hyphae transition, biofilm formation and cell adherence. An in vivo study was also performed in a Caenorhabditis elegans infection model. Results: Mg chelation leads to potentiation of membrane-targeting antifungals. The role of Mg on membrane homeostasis was explored and significant differences in ergosterol levels were found. Interestingly, it was also observed that Mg deprivation impedes the metabolic flexibility of C. albicans SC5314 by inhibiting glyoxylate cycle enzymes. Furthermore, Mg deprivation inhibited potential virulence traits, including morphological transition, biofilm formation and buccal epithelial cell adherence. All of the disrupted gene targets were validated by reverse transcription PCR. Lastly, enhanced survival of C. elegans infected with C. albicans SC5314 under Mg deprivation was observed. Conclusion: In view of the restricted growth of C. albicans in a Mg-deficient environment, approaches could be utilised to boost the effectiveness of existing antifungals thereby improving the management of fungal infections. (C) 2019 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.