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

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 a...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2018-08, Vol.62 (8)
Main Authors: Savage, Kimberley A, Parquet, Maria del Carmen, Allan, David S, Davidson, Ross J, Holbein, Bruce E, Lilly, Elizabeth A, Fidel, Jr, Paul L
Format: Article
Language:English
Subjects:
Animals
Antifungal Agents
Antifungal Agents - therapeutic use
Azoles
Azoles - therapeutic use
Candida - drug effects
Candida - pathogenicity
Candida albicans
Candida albicans - drug effects
Candida albicans - pathogenicity
Deferiprone - therapeutic use
Deferoxamine - therapeutic use
Disease Models, Animal
Drug Resistance, Fungal
Drug Synergism
Experimental Therapeutics
Female
Mice
Vaginitis
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Summary: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 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 DIBI, but not deferoxamine or deferiprone, inhibited the growth of at relatively low concentrations , 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 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.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.02576-17