Components of the Calcium-Calcineurin Signaling Pathway in Fungal Cells and Their Potential as Antifungal Targets

Abstract

dIn recent years, the emergence of fungal resistance has become frequent, partly due to the widespread clinical use of fluconazole, which is minimally toxic and effective in the prevention and treatment of Candida albicans infections. The limited selection of antifungal drugs for clinical fungal infection therapy has prompted us to search for new antifungal drug targets. Calcium, which acts as the second messenger in both mammals and fungi, plays a direct role in controlling the expression patterns of its signaling systems and has important roles in cell survival. In addition, calcium and some of the components, mainly calcineurin, in the fungal calcium signaling pathway mediate fungal resistance to antifungal drugs. Therefore, an overview of the components of the fungal calcium-calcineurin signaling network and their potential roles as antifungal targets is urgently needed. The calciumcalcineurin signaling pathway consists of various channels, transporters, pumps, and other proteins or enzymes. Many transcriptional profiles have indicated that mutant strains that lack some of these components are sensitized to fluconazole or other antifungal drugs. In addition, many researchers have identified efficient compounds that exhibit antifungal activity by themselves or in combination with antifungal drugs by targeting some of the components in the fungal calcium-calcineurin signaling pathway. This targeting disrupts Ca 2؉ homeostasis, which suggests that this pathway contains potential targets for the development of new antifungal drugs.

Osmoregulation in Saccharomyces cerevisiae via mechanisms other than the high-osmolarity glycerol pathway

“…Owing to the evolutionary conservation of several mechanisms of stress responses in a wide range of organisms, both unicellular and multicellular, these studies additionally enable us to make testable predictions and formulate experimental strategies in other organisms that are less well-characterized or otherwise experimentally less tractable owing to a variety of reasons. For example, molecular components mediating stress responses in pathogenic fungi can serve as potential targets for antifungals, as well as provide important information on the mode of antifungal action (recently reviewed by Brown et al, 2014;Hayes et al, 2014;Thewes, 2014;Liu et al, 2015). Studies of TOR signalling in yeast in the context of lifespan extension by calorie restriction have uncovered previously unanticipated mechanisms, which are stress responsive and mediated by sirtuin-2, of suppressing genomic instability arising from repetitive ribosomal DNA (Medvedik et al, 2007;see Schleit et al, 2012, for a review).…”

Calcineurin in fungal virulence and drug resistance: Prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach

“…10 Calcineurin has been identified as one of the important regulators of intracellular calcium homeostasis in several fungi. 11 Furthermore, antifungal resistance has also been linked to calcium and calcineurin signaling cascade.…”

“…11 Furthermore, antifungal resistance has also been linked to calcium and calcineurin signaling cascade. 10,12 For example, combinations of calcium and calcineurin inhibitors with known antifungal compounds have been shown to inhibit the growth of drug resistant fungal strains. [13][14][15][16][17][18][19] Therefore, inhibition of calcineurin signaling is a novel antifungal strategy that both attenuates fungal virulence and increases the efficacy of the existing antifungals with concomitant suppression of antifungal resistance.…”

“…[13][14][15][16][17][18][19] Therefore, inhibition of calcineurin signaling is a novel antifungal strategy that both attenuates fungal virulence and increases the efficacy of the existing antifungals with concomitant suppression of antifungal resistance. 10,20,21 Calcineurin is a conserved Ca 2C -calmodulin (CaM) activated protein phosphatase 2B belonging to the phospho-protein phosphatase family of enzymes and is involved in calcium-dependent signaling and regulation of several important cellular processes in both yeasts and filamentous fungi (Fig. 1).…”

Microencapsulation of Baker’s Yeast in Gellan Gum Beads Used in Repeated Cycles of Glucose Fermentation

“…The calcium ions, in high concentrations, can replace the magnesium in a number of biochemical processes which can lead to cell growth and to maintaining the cell viability. Also, increasing the calcium concentration in the fermentation medium has a buffer effect which prevents the increase of pH in the environment and leads to an increased fermentation efficiency [41,42]. The originality of this study is primarily related to the pregelification of the gellan solution, before the capillary extrusion, using low concentrations of CaCl 2 which leads to a viscosity increase of the polysaccharide solution.…”