title: Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin.
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.
authors.affiliation: Institut Pasteur, Cytokines & Inflammation, Département Infection & Epidemiology, Paris, France.
authors.forename: Paris
authors.initials: P
authors.lastname: Laskaris
authors.affiliation: Institut Pasteur, Cytokines & Inflammation, Département Infection & Epidemiology, Paris, France.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Atrouni
authors.affiliation: Universidad de Salamanca, Instituto de Biologia Funcional y Genómica, Departamento de Microbiología y Genética, Salamanca, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Calera
authors.affiliation: Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Mycologie, Paris, France INRA, USC2019, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: d'Enfert
authors.affiliation: Institut Pasteur, Unité de Chimie et Biocatalyse, CNRS UMR3523, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.affiliation: Institut Pasteur, Cytokines & Inflammation, Département Infection & Epidemiology, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.affiliation: Institut Pasteur, Unité des Aspergillus, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latgé
authors.affiliation: Institut Pasteur, Cytokines & Inflammation, Département Infection & Epidemiology, Paris, France ogranet@pasteur.fr.
authors.forename: Oumaïma
authors.initials: O
authors.lastname: Ibrahim-Granet
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D000077336:Caspofungin; D002614:Chelating Agents / Q000494:pharmacology*; D007464:Clioquinol / Q000494:pharmacology; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000494:pharmacology*; D005021:Ethylamines / Q000494:pharmacology; D007106:Immune Sera / Q000494:pharmacology; D016867:Immunocompromised Host; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D008807:Mice, Inbred BALB C; D010618:Phenanthrolines / Q000494:pharmacology; D011014:Pneumonia / Q000382:microbiology / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D016896:Treatment Outcome; D015032:Zinc
chemical_list: D000935:Antifungal Agents; D002614:Chelating Agents; D054714:Echinocandins; D005021:Ethylamines; D007106:Immune Sera; D055666:Lipopeptides; C511824:N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine; D010618:Phenanthrolines; D011725:Pyridines; D007464:Clioquinol; D000077336:Caspofungin; D015032:Zinc; C025205:1,10-phenanthroline