Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis

Abstract

Candida albicans, the causative agent of mucosal infections, including oropharyngeal candidiasis (OPC), as well as bloodstream infections, is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off-label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence, while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth. Here we evaluated the role of iron limitation using deferasirox (an FDA-approved iron chelator for the treatment of patients with iron overload) during murine OPC and assessed deferasirox-treated C. albicans for its interaction with human oral epithelial (OE) cells, neutrophils, and antimicrobial peptides. Therapeutic deferasirox treatment significantly reduced salivary iron levels, while a nonsignificant reduction in the fungal burden was observed. Preventive treatment that allowed for two additional days of drug administration in our murine model resulted in a significant reduction in the number of C. albicans CFU per gram of tongue tissue, a significant reduction in salivary iron levels, and significantly reduced neutrophil-mediated inflammation. C. albicans cells harvested from the tongues of animals undergoing preventive treatment had the differential expression of 106 genes, including those involved in iron metabolism, adhesion, and the response to host innate immunity. Moreover, deferasirox-treated C. albicans cells had a 2-fold reduction in survival in neutrophil phagosomes (with greater susceptibility to oxidative stress) and reduced adhesion to and invasion of OE cells in vitro. Thus, deferasirox treatment has the potential to alleviate OPC by affecting C. albicans gene expression and reducing virulence.

CO2enhances the ability ofCandida albicansto form biofilms, overcome nutritional immunity and resist antifungal treatment

“…We therefore wished to test whether these represented potential targets to combat C. albicans growth in high CO 2 environments such as the airway. An Fe 3+ chelator called Deferasirox, which is approved for treating patients with iron overload, has recently been shown to reduce infection levels in a murine oropharyngeal candidiasis model 63 . With this in mind, we repeated our previous iron starvation biofilm growth assay (Figure 4B) using Deferasirox in place of Ferrozine.…”

Gemini quaternary ammonium compound PMT12-BF4 inhibits Candida albicans via regulating iron homeostasis

“…As discussed by Puri et al (2019), iron-related regulation in C. albicans is mainly mediated by four regulators, Tup1, Hap43, Sfu1 and Sef1 22 . Our mutant library screening data demonstrated that PMT12-BF4-associated iron-related genes were regulated by these regulators, and most of these genes were repressed by Hap43, indicating the antifungal activity of PMT12-BF4 may not directly alter the iron concentration in the environment, but instead, it possibly interferes with functions of iron regulation.…”

Impact of the repurposed drug thonzonium bromide on host oral-gut microbiomes

“…Drug repurposing has been proposed as an alternative for new therapeutic applications using FDA-approved drugs 1 . Repurposed drugs have been explored as antimicrobial treatments to target pathogens [33][34][35][36][37] . Previously, either free or nanoparticle carrier (NPC) loaded TB was tested for repurposing as antimycotic and antibacterial agents, with promising in vitro data 19,30 .…”