DTPA enhances caspofungin activity via depletion of magnesium.
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A) DTPA enhances the efficacy of caspofungin against an echinocandin-resistant clinical isolate, while ciclopirox ethanolamine does not. A dose response matrix (checkerboard assay) was performed in synthetic defined medium with gradients of caspofungin and DTPA or the iron chelator ciclopirox ethanolamine, as indicated. Data was analyzed after 72 hours at 30°C, and analyzed as in Fig 1A. B) Depleting magnesium impairs growth of a clinical isolate in caspofungin (P<0.001, two-way ANOVA, Bonferroni correction). Chelex 100 resin was used to deplete synthetic defined medium of its metal components. Metals were restored based on the concentrations at which they are normally present in yeast nitrogen base, restoring each individual metal as indicated. After 24 hours, optical density at 600 nm was assessed in each medium, in the absence or presence of 2 μg/mL caspofungin. Data are means ± SD for triplicate samples and are representative of two independent experiments. C) Addition of magnesium to metal-depleted medium best restores echinocandin resistance of the clinical isolate (P<0.001, two-way ANOVA, Bonferroni correction). Assay was performed and analyzed as in Fig 2B.