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

Antimicrob Agents Chemother. 2016 Sep 23;60(10):5631-9. doi: 10.1128/AAC.00324-16. Print 2016 Oct.

Abstract

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.

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology*
  • Aspergillosis / drug therapy*
  • Aspergillosis / immunology
  • Aspergillosis / microbiology
  • Aspergillosis / mortality
  • Aspergillus fumigatus / drug effects*
  • Aspergillus fumigatus / growth & development
  • Aspergillus fumigatus / pathogenicity
  • Caspofungin
  • Chelating Agents / pharmacology*
  • Clioquinol / pharmacology
  • Drug Therapy, Combination
  • Echinocandins / pharmacology*
  • Ethylamines / pharmacology
  • Immune Sera / pharmacology
  • Immunocompromised Host
  • Lipopeptides / pharmacology*
  • Male
  • Mice, Inbred BALB C
  • Phenanthrolines / pharmacology
  • Pneumonia / microbiology
  • Pneumonia / pathology
  • Pyridines / pharmacology
  • Treatment Outcome
  • Zinc

Substances

  • Antifungal Agents
  • Chelating Agents
  • Echinocandins
  • Ethylamines
  • Immune Sera
  • Lipopeptides
  • N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine
  • Phenanthrolines
  • Pyridines
  • Clioquinol
  • Caspofungin
  • Zinc
  • 1,10-phenanthroline

Grant support

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.