Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans

Abstract

Curcumin (CUR) shows antifungal activity against a range of pathogenic fungi, including Candida albicans. The reported mechanisms of action of CUR include reactive oxygen species (ROS) generation, defects in the ergosterol biosynthesis pathway, decrease in hyphal development, and modulation of multidrug efflux pumps. Reportedly, each of these pathways is independently linked to the cell wall machinery in C. albicans, but surprisingly, CUR has not been previously implicated in cell wall damage. In the present study, we performed transcriptional profiling to identify the yet-unidentified targets of CUR in C. albicans. We found that, among 348 CUR-affected genes, 51 were upregulated and 297 were downregulated. Interestingly, most of the cell wall integrity pathway genes were downregulated. The possibility of the cell wall playing a critical role in the mechanism of CUR required further validation; therefore, we performed specific experiments to establish if there was any link between the two. The fractional inhibitory concentration index values of 0.24 to 0.37 show that CUR interacts synergistically with cell wall-perturbing (CWP) agents (caspofungin, calcofluor white, Congo red, and SDS). Furthermore, we could observe cell wall damage and membrane permeabilization by CUR alone, as well as synergistically with CWP agents. We also found hypersusceptibility in calcineurin and mitogen-activated protein (MAP) kinase pathway mutants against CUR, which confirmed that CUR also targets cell wall biosynthesis in C. albicans. Together, these data provide strong evidence that CUR disrupts cell wall integrity in C. albicans. This new information on the mechanistic action of CUR could be employed in improving treatment strategies and in combinatorial drug therapy.

In vitro Evaluation of the Curcumin against Fluconazole-Resistant Strains of Candida spp. and Cryptococcus neoformans

“…Recently, Kumar et al, (2014) reported that after treatment with curcumin alone or associated with antifungal in C. albicans cells, there was an increase in the membrane permeabilization to the PI dye, which agrees with our results, where the fungal growth and the development and the ability to survive under environmental stress conditions are dependent on the integrity of the membrane and the cell wall. The effects of 24 h incubations with RPMI-1640 (control), with FLC (64 µg/mL), Ampho (4 µg/mL) and curcumin at concentrations of MIC, 2x MIC, 4x MIC on the DNA damage index in C. albicans.…”

“…It is important to stand out that structural modification in the nucleotide bases may occur as a result of oxidative stress. Several studies point to the role of reactive oxygen species (ROS's) in the mechanism of action of curcumin (Kumar et al, 2014;Sharma et al, 2010).…”

A P4-ATPase subunit of the Cdc50 family plays a role in iron acquisition and virulence inCryptococcus neoformans

“…Curcumin is a chelator of Fe(III) that antagonizes the growth of S . cerevisiae and Candida albicans (Azad, Singh, Thakare, Baranwal, & Tomar, ; Carmello, Pavarina, Oliveira, & Johansson, ; Kumar et al, ; Lee & Lee, ; Minear et al, ; Neelofar et al, ). Interestingly, a screen of the S .…”

“…Curcumin is a chelator of Fe(III) that antagonizes the growth of S. cerevisiae and Candida albicans (Azad, Singh, Thakare, Baranwal, & Tomar, 2014;Carmello, Pavarina, Oliveira, & Johansson, 2015;Kumar et al, 2014;Lee & Lee, 2014;Minear et al, 2011;Neelofar et al, 2011). Interestingly, a screen of the S. cerevisiae deletion collection for sensitivity to curcumin identified mutants lacking iron uptake functions and the Lem3 subunit of flippases (Azad et al, 2014).…”

Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis

“…So far, few compounds have shown antifungal activity by interfering with CWI response, instead of targeting individual structural components of the cell wall. For example, curcumin (a mixture of curcuminoids extracted from the rhizome of the perennial herb Curcuma longa) has been shown to affect cell wall structure in Candida albicans by down-regulating the expression of different chitin synthase genes, possibly by inhibiting CWI signaling (Kumar et al 2014). Similarly, farnesol seems to interfere with growth of Aspergillus fumigatus hyphae by misplacing the Rho1 protein, originally concentrated at hyphal tips, where it controls cell wall remodeling in response to fungal development (Dichtl et al 2010).…”