Copper Homeostasis in Aspergillus fumigatus: Opportunities for Therapeutic Development

Conclusions Because the expression of copper tolerance genes is critical for the survival and virulence of fungal pathogens, pharmacological disruption of the function of copper tolerance genes would be predicted to have the following beneficial effects: (1) Induce fungal death: the loss of copper tolerance genes would lead to toxic levels of copper that would be expected to have fungistatic and/or fungicidal effects on the organism. (2) Enhance the activity of current antifungal drugs: the clinical efficacy of current antifungal drugs may be compromised by intrinsic or acquired resistance. Combination antifungal therapy with agents of different mechanistic classes could promote fungal killing and clinical efficacy and provide an alternative to monotherapy regimens. This suggests that combining inhibitors of copper tolerance proteins with one or more current antifungals could increase efficacy, promote fungal killing, and prevent the emergence of drug resistance more effectively than monotherapy regimens. In particular, combination therapy might reduce the hepatotoxicity caused by long-term exposure to high doses of azoles drugs. Thus, the AfAceA and crpA copper tolerance genes may be potential drug targets, although deletion of these genes in A. fumigatus leads only to attenuated virulence, not avirulence. Taken together, the regulation of copper homeostasis provides promising therapeutic targets for combating A. fumigatus infection. Furthermore, by targeting copper homeost...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research