Copper Availability Influences the Transcriptomic Response of Candida albicans to Fluconazole Stress.

The ability of pathogens to maintain homeostatic levels of essential biometals is known to be important for survival and virulence in a host, which itself regulates metal availability as part of its response to infection. Given this importance of metal homeostasis, we sought to address how the availability of copper in particular impacts the response of the opportunistic fungal pathogen Candida albicans to treatment with the antifungal drug fluconazole. The present study reports whole transcriptome analysis via time-course RNA-seq of C.

Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans.

Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent.

Candida albicans reprioritizes metal handling during fluconazole stress.

Maintenance of metal homeostasis is critical to cell survival due to the multitude of cellular processes that depend on one or more metal cofactors. Here, we show that the opportunistic fungal pathogen Candida albicans extensively remodels its metal homeostasis networks to respond to treatment with the antifungal drug fluconazole. Disruption of the ergosterol biosynthetic pathway by fluconazole requires C.

Emerging Opportunities To Manipulate Metal Trafficking for Therapeutic Benefit.

The indispensable requirement for metals in life processes has led to the evolution of sophisticated mechanisms that allow organisms to maintain dynamic equilibria of these ions. This dynamic control of the level, speciation, and availability of a variety of metal ions allows organisms to sustain biological processes while avoiding toxicity. When functioning properly, these mechanisms allow cells to return to their metal homeostatic set points following shifts in the metal availability or other stressors.

Copper potentiates azole antifungal activity in a way that does not involve complex formation.

To survive, fungal pathogens must acquire nutrient metals that are restricted by the host while also tolerating mechanisms of metal toxicity that are induced by the host. Given this dual vulnerability, we hypothesized that a pathogen's access to and control of essential yet potentially dangerous metal ions would affect fungal tolerance to antifungal drug stress. Here, we show that Candida albicans becomes sensitized to both Cu limitation and Cu elevation during exposure in liquid culture to the antifungal drug fluconazole, a widely prescribed antifungal agent.