Antifungal activities of natural and synthetic iron chelators alone and in combination with azole and polyene antibiotics against Aspergillus fumigatus

Abstract

Antifungal effects of iron chelators (lactoferrin, deferoxamine, deferiprone, and ciclopirox) were tested alone and in combination with antifungal drugs against Aspergillus fumigatus B5233 conidia. Lactoferrin, ciclopirox, and deferiprone inhibited whereas deferoxamine enhanced fungal growth. Antifungal synergy against conidia was observed for combinations of ketoconazole with ciclopirox or deferiprone, lactoferrin with amphotericin B, and fluconazole with deferiprone. Iron chelation alone or combined with antifungal drugs may be useful for prevention and treatment of mycosis.

FIG. 1.

Iron chelator effect on Aspergillus fumigatus conidial growth. Fungal growth inhibition was performed as described in the text, and the data are expressed as percentages of control growth in vehicle alone. Dose-response curves were estimated from multiple experiments (for deferoxamine, n = 3; for deferiprone, n = 38; for ciclopirox, n = 40; for lactoferrin, n = 43) using three-parameter logistic models and are plotted with 95% confidence intervals.

FIG. 2.

Isobolograms of combined antifungal effects. The doses of each agent alone (indicated by Z_A and Z_B) and in combination, indicated by (, ), required to achieve a 50% reduction in growth compared to that of untreated controls are plotted along with the 95% confidence intervals. Under additivity, the dose pair (, ) is expected to yield the same effect. Lines of additivity are indicated by open triangles, and measured drug combinations are indicated by filled circles. Statistical significance (P < 0.05) is indicated by an asterisk, and the P value of the global chi-square test is given in the upper right corner of each graph. Panels A to D show examples of synergistic combinations of chelators with antifungal drugs. The figures are generated from between four and eight checkerboard experiments for each combination of drugs.