Abstract
Candida albicans causes superficial to systemic infections in immuno-compromised individuals. The concomitant use of fungistatic drugs and the lack of cidal drugs frequently result in strains that could withstand commonly used antifungals, and display multidrug resistance (MDR). In search of novel fungicidals, in this study, we have explored a plant alkaloid berberine (BER) for its antifungal potential. For this, we screened an in-house transcription factor (TF) mutant library of C. albicans strains towards their susceptibility to BER. Our screen of TF mutant strains identified a heat shock factor (HSF1), which has a central role in thermal adaptation, to be most responsive to BER treatment. Interestingly, HSF1 mutant was not only highly susceptible to BER but also displayed collateral susceptibility towards drugs targeting cell wall (CW) and ergosterol biosynthesis. Notably, BER treatment alone could affect the CW integrity as was evident from the growth retardation of MAP kinase and calcineurin pathway null mutant strains and transmission electron microscopy. However, unlike BER, HSF1 effect on CW appeared to be independent of MAP kinase and Calcineurin pathway genes. Additionally, unlike hsf1 null strain, BER treatment of Candida cells resulted in dysfunctional mitochondria, which was evident from its slow growth in non-fermentative carbon source and poor labeling with mitochondrial membrane potential sensitive probe. This phenotype was reinforced with an enhanced ROS levels coinciding with the up-regulated oxidative stress genes in BER-treated cells. Together, our study not only describes the molecular mechanism of BER fungicidal activity but also unravels a new role of evolutionary conserved HSF1, in MDR of Candida.
Highlights
Candida albicans is a part of normal commensal flora of human body, which becomes one of the most resilient fungal pathogen under low host immunity [1], [2]
C. utilis, C. kefyr and C. krusei were relatively hypersusceptible to BER and their MIC50 ranged between 25 mg/ml and .50 mg/ml, while C. glabrata and C. tropicalis were the least susceptible species with MIC50 of 200 mg/ml in contrast to C. albicans
BER treatment affects the calcineurin pathway and cell wall (CW) integrity leading to dysfunctional mitochondria and cell death
Summary
Candida albicans is a part of normal commensal flora of human body, which becomes one of the most resilient fungal pathogen under low host immunity [1], [2]. Available antifungals predominantly include azoles, echinocandins, polyenes and allylamines [3]. Each of these classes of antifungals have a distinct mode of action, for example azoles target heme protein, cytochrome P450 lanosterol 14 a demethylase thereby impeding conversion of lanosterol to fecosterol and subsequently blocking ergosterol biosynthesis [4]. Echinocandins interfere with CW synthesis by inhibiting b1-3 glucan synthase [5]. Polyenes have affinity to bind membrane sterols that results in the formation of aqueous pores ensuing the leakage of crucial cellular components and subsequent cell death [6]. Allylamines are relatively newer class of antifungal that inhibit ergosterol biosynthesis but by targeting squalene epoxidase [7]
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