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. 2018 Jul 27;62(8):e02576-17.
doi: 10.1128/AAC.02576-17. Print 2018 Aug.

Iron Restriction to Clinical Isolates of Candida Albicans by the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to Azoles In Vitro and In Vivo in a Murine Model of Experimental Vaginitis

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Iron Restriction to Clinical Isolates of Candida Albicans by the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to Azoles In Vitro and In Vivo in a Murine Model of Experimental Vaginitis

Kimberley A Savage et al. Antimicrob Agents Chemother. .
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Abstract

Candida albicans is an important opportunistic pathogen causing various human infections that are often treated with azole antifungals. The U.S. CDC now regards developing candidal antifungal resistance as a threat, creating a need for new and more effective antifungal treatments. Iron is an essential nutrient for all living cells, and there is growing evidence that interference with iron homeostasis of C. albicans can improve its response to antifungals. This study was aimed at establishing whether withholding iron by currently used medical iron chelators and the novel chelator DIBI could restrict growth and also enhance the activity of azoles against clinical isolates of C. albicans DIBI, but not deferoxamine or deferiprone, inhibited the growth of C. albicans at relatively low concentrations in vitro, and this inhibition was reversed by iron addition. DIBI in combination with various azoles demonstrated stronger growth inhibition than the azoles alone and greatly prolonged the inhibition of cell multiplication. In addition, the administration of DIBI along with fluconazole (FLC) to mice inoculated with an FLC-sensitive isolate in a model of experimental C. albicans vaginitis showed a markedly improved clearance of infection. These results suggest that iron chelation by DIBI has the potential to enhance azole efficacy for the treatment of candidiasis.

Keywords: Candida albicans; DIBI; antifungal agents; azoles; iron; synergy.

Figures

FIG 1
FIG 1
Structures of deferiprone and DIBI. Deferiprone is a hydroxypyridinone iron chelator (molecular mass, 139 Da) with similar chelating functionality to DIBI, an iron-chelating polymer (molecular mass, 9 kDa) containing 9 hydroxypyridinone groups per molecule.
FIG 2
FIG 2
DIBI growth inhibition of C. albicans is iron reversible. RPMI (✳), RPMI with DIBI at 1 (△) or 10 μg/ml (□), and RPMI supplemented with 1 μM iron with DIBI at 1 (▲) or 10 μg/ml (■) were inoculated with C. albicans strain Ca3969. Growth was measured as OD at 600 nm over 48 h. Data points are means ± SEMs from 2 independent experiments. *, P < 0.05 for DIBI 1 or 10 μg/ml or RPMI plus iron plus DIBI 10 μg/ml versus RPMI, for DIBI 1 μg/ml versus DIBI 10 μg/ml, for DIBI 1 μg/ml versus RPMI plus iron plus DIBI 1 μg/ml, and for DIBI 10 μg/ml versus RPMI plus iron plus DIBI 10 μg/ml.
FIG 3
FIG 3
Recovery growth of C. albicans is inhibited after exposure to a combination of fluconazole (FLC) and DIBI. A 5-μl volume from each well of a checkerboard assay that had been inoculated with Ca5031 was spotted onto a YPD agar plate following 24-h (A) or 48-h (B) exposure to the agent. Recovery plates were incubated for 24 h before being visually inspected and photographed. Images are representative of results observed in 3 independent experiments.
FIG 4
FIG 4
Long-term growth inhibition of C. albicans by combinations of DIBI with fluconazole (FLC), itraconazole (ITC), and clotrimazole (CLT). RPMI (formula image), RPMI with DIBI alone (△), RPMI with azole alone (○), and RPMI with DIBI and azole combined (◊) were inoculated with azole-susceptible strains (96113, Ca3969, Ca5031) or the FLC-resistant isolate (LP1158-07), as indicated. (A) 1 μg/ml DIBI, 1 μg/ml FLC; (B) 10 μg/ml DIBI, 128 μg/ml FLC; (C) 10 μg/ml DIBI, 0.5 μg/ml ITC; (D) 10 μg/ml DIBI, 0.25 μg/ml ITC; (E and F) 10 μg/ml DIBI, 0.03 μg/ml CLT. Viable cell counts were determined by plate counting over 72 h. Data points are means ± SEMs from 3 independent experiments. *, P < 0.01 for DIBI plus azole versus RPMI, DIBI alone, or azole alone.
FIG 5
FIG 5
Improvement of fluconazole (FLC) by DIBI in vivo. Experimental murine vaginitis was established using FLC-sensitive strain 96113. Animals were given DIBI alone (40 mg/kg), FLC alone (25 mg/kg), or a combination of DIBI plus FLC. Vaginal fungal burden was evaluated at day 7 postinoculation. Results are expressed as CFU/100 μl vaginal lavage fluid. Percentages indicate rates of fungal clearance. Results are cumulative of 5 independent experiments.

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