Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

Abstract

f Aspergillus fumigatus can infect immunocompromised patients, leading to high mortality rates due to the lack of reliable treatment options. This pathogen requires uptake of zinc from host tissues in order to successfully grow and cause virulence. Reducing the availability of that micronutrient could help treat A. fumigatus infections. In this study, we examined the in vitro effects of seven chelators using a bioluminescent strain of A. fumigatus. 1,10-Phenanthroline and N,N,N=,N=-tetrakis(2-pyridylmethyl) ethane-1,2-diamine (TPEN) proved to be the chelators most effective at inhibiting fungal growth. Intraperitoneal administration of either phenanthroline or TPEN resulted in a significant improvement in survival and decrease of weight loss and fungal burden for immunosuppressed mice intranasally infected with A. fumigatus. In vitro both chelators had an indifferent effect when employed in combination with caspofungin. The use of TPEN in combination with caspofungin also significantly increased survival compared to that when using these drugs individually. Our results suggest that zinc chelation may be a valid strategy for dealing with A. fumigatus infections and that both phenanthroline and TPEN could potentially be used either independently or in combination with caspofungin, indicating that their use in combination with other antifungal treatments might also be applicable.A spergillus fumigatus is a widespread soil-dwelling fungal saprotroph (1). It is one of the most ubiquitous fungal species with airborne conidia, and it is estimated that all humans inhale several hundred conidia each day (2). These are completely innocuous to immunocompetent hosts. However, the conidia are able to develop and cause invasive pulmonary aspergillosis (IPA) in immunocompromised individuals (3). This disease is difficult to treat, with a mortality rate of 45.6% (4). Commonly used drug treatment options include triazoles such as voriconazole, which inhibit ergosterol synthesis, amphotericin B, which binds to ergosterol and thus results in increased permeability of the cell membrane, and echinocandins such as caspofungin, which inhibit glucan synthesis (5).Both fungal and bacterial pathogens require cations to grow within their hosts and utilize specialized mechanisms in order to obtain them (6). Zinc is considered essential for all organisms, including pathogens (7). The average concentration of free Zn 2ϩ in human serum is 0.08 M, which is about 150 times lower than the minimal concentration required for A. fumigatus to grow optimally in a defined liquid medium (8). A. fumigatus possesses three genes, zrfA, zrfB, and zrfC, encoding plasma membrane zinc transporters (8). The zrfA and zrfB genes are required for zinc uptake in acidic Zn-limited environments (7), while zrfC is required for zinc uptake in alkaline environments (9) The zrfC gene is primarily responsible for zinc acquisition within a host's lungs and is required for virulence; zrfA and zrfB contribute to fungal pathogenesis to a lesser extent than zrfC and are not r...

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

“…It is plausible that this redistribution may create a transient state of zinc deficiency during acute viral infections which may indirectly protect cells by inducing an antiviral state. It has been suggested that pathogens may actively alter zinc levels and zinc chelation with TPEN was shown to improve survival of mice infected with Aspergillus fumigatus (59). In the case of HIV, zinc chelation by TPEN was shown to inhibit APOBEC3 degradation by HIV-1Vif and made the virus susceptible to the antiviral activity of APOBEC3 (60).…”

N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine, a zinc chelator, inhibits biofilm and hyphal formation in Trichosporon asahii

“…TPEN has been used as a zinc chelator in several studies [15][16][17]. Therefore, we tested the effect of zinc on biofilm formation by T. asahii.…”

“…Depletion of divalent cations, such as iron, calcium, and magnesium, inhibit biofilm formation by Aspergillus fumigatus and Cryptococcus neoformans [19,20]. In a murine model of invasive pulmonary aspergillosis caused by pathogenic fungus Aspergillus fumigatus, TPEN improved survival [16]. In vivo experiments to evaluate the inhibitory effect of TPEN on biofilm formation by T. asahii are areas for future research.…”

Comparative Study of Pathogenicity Between Aspergillus Fumigatus and Penicillium Chrysogenum in Mice

“…A. fumigatus is considered one of the most common saprophytic fungi in the environment, and in the same time, It is opportunistic pathogen can cause different types of mycosis ranging from allergy to invasive and fatal disseminated Aspergillosis through it's presence as ubiquitous airborne conidia (7,15,16), So, there are many studies were performed to determine effect of A. fumigatus when inoculated intranasally into mice and conducted to that the normal host can be suffering from systemic Aspergillosis ( 13,14,25). But the present study focused on the efficacy this type of fungi on the some internal organs when adminis-tered intraperitonially into mice as a sequel to disseminated Aspergillosis.…”