Insights into the modulatory effect of magnesium on efflux mechanisms of Candida albicans reveal inhibition of ATP binding cassette multidrug transporters and dysfunctional mitochondria

• Published in: Biometals Vol. 34; no. 2; pp. 329 - 339
• Main Authors: Hans, Sandeep, Fatima, Zeeshan, Hameed, Saif
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.04.2021; Springer Nature B.V
• Subjects: ATP; Binding; Biochemistry; Biomedical and Life Sciences; Candida albicans; Cell Biology; Complementarity-determining region 1; Depletion; Deprivation; Efflux; Ergosterol; Fungicides; Homeostasis; Life Sciences; Magnesium; Medicine/Public Health; Microbiology; Mitochondria; Multidrug resistance; Pharmacology/Toxicology; Plant Physiology; Public health; Rhodamine 6G; Ergosterol; Mitochondria; MDR; ABC transporters; Magnesium; Drug efflux; Candida albicans
• ISSN: 0966-0844; 1572-8773
• DOI: 10.1007/s10534-020-00282-w

Candida infections pose a serious hazard to public health followed by widespread and prolonged deployment of antifungal drugs has which has led multidrug resistance (MDR) progress in prevalent human fungal pathogen, Candida albicans . Despite the fact that MDR is multifactorial phenomenon govern by several mechanisms in C. albicans , overexpression of drug efflux transporters by far remains the leading cause of MDR govern by ATP Binding Cassette (ABC) or major facilitator superfamily (MFS) transporters. Hence searching for strategies to target efflux pumps transporter still signifies a promising approach. In this study we analyzed the effect of magnesium (Mg) deprivation, on efflux pump action of C. albicans . We explored that Mg deprivation specially inhibits efflux of transporters (CaCdr1p and CaCdr2p) belonging to ABC superfamily as revealed by rhodamine 6G and Nile red accumulation. Furthermore, Mg deprivation causes mislocalization of CaCdr1p and CaCdr2p and reduced transcripts of CDR1 and CDR2 with no effect on CaMdr1p. Additionally, Mg deprivation causes depletion of ergosterol content in azole sensitive and resistant clinical matched pair of isolates Gu4/Gu5 and F2/F5 of C. albicans . Lastly, we observed that Mg deprivation impairs mitochondrial potential which could be the causal reason for abrogated efflux activity. With growing appreciation of manipulating metal homeostasis to combat MDR, inhibition of efflux activity under Mg deprivation warrants further studies to be utilized as an effective antifungal strategy.