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Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy

An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well as resistance to the currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism of action. Here we report the identification and characterization of two novel zinc-atten...

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Autores principales: Cohrt, Karen A. O'Hanlon, Marín, Laura, Kjellerup, Lasse, Clausen, Johannes D., Dalby-Brown, William, Calera, José Antonio, Winther, Anne-Marie Lund
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923171/
https://www.ncbi.nlm.nih.gov/pubmed/29439980
http://dx.doi.org/10.1128/AAC.02024-17
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author Cohrt, Karen A. O'Hanlon
Marín, Laura
Kjellerup, Lasse
Clausen, Johannes D.
Dalby-Brown, William
Calera, José Antonio
Winther, Anne-Marie Lund
author_facet Cohrt, Karen A. O'Hanlon
Marín, Laura
Kjellerup, Lasse
Clausen, Johannes D.
Dalby-Brown, William
Calera, José Antonio
Winther, Anne-Marie Lund
author_sort Cohrt, Karen A. O'Hanlon
collection PubMed
description An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well as resistance to the currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism of action. Here we report the identification and characterization of two novel zinc-attenuating compounds, ZAC307 and ZAC989, which exhibit broad-spectrum in vitro antifungal activity and in vivo efficacy in a fungal kidney burden candidiasis model. The compounds were identified serendipitously as part of a drug discovery process aimed at finding novel inhibitors of the fungal plasma membrane proton ATPase Pma1. Based on their structure, we hypothesized that they might act as zinc chelators. Indeed, both fluorescence-based affinity determination and potentiometric assays revealed these compounds, subsequently termed zinc-attenuating compounds (ZACs), to have strong affinity for zinc, and their growth inhibitory effects on Candida albicans and Aspergillus fumigatus could be inactivated by the addition of exogenous zinc to fungal growth media. We determined the ZACs to be fungistatic, with a low propensity for resistance development. Gene expression analysis suggested that the ZACs interfere negatively with the expression of genes encoding the major components of the A. fumigatus zinc uptake system, thus supporting perturbance of zinc homeostasis as the likely mode of action. With demonstrated in vitro and in vivo antifungal activity, low propensity for resistance development, and a novel mode of action, the ZACs represent a promising new class of antifungal compounds, and their advancement in a drug development program is therefore warranted.
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spelling pubmed-59231712018-05-11 Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy Cohrt, Karen A. O'Hanlon Marín, Laura Kjellerup, Lasse Clausen, Johannes D. Dalby-Brown, William Calera, José Antonio Winther, Anne-Marie Lund Antimicrob Agents Chemother Mechanisms of Action: Physiological Effects An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well as resistance to the currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism of action. Here we report the identification and characterization of two novel zinc-attenuating compounds, ZAC307 and ZAC989, which exhibit broad-spectrum in vitro antifungal activity and in vivo efficacy in a fungal kidney burden candidiasis model. The compounds were identified serendipitously as part of a drug discovery process aimed at finding novel inhibitors of the fungal plasma membrane proton ATPase Pma1. Based on their structure, we hypothesized that they might act as zinc chelators. Indeed, both fluorescence-based affinity determination and potentiometric assays revealed these compounds, subsequently termed zinc-attenuating compounds (ZACs), to have strong affinity for zinc, and their growth inhibitory effects on Candida albicans and Aspergillus fumigatus could be inactivated by the addition of exogenous zinc to fungal growth media. We determined the ZACs to be fungistatic, with a low propensity for resistance development. Gene expression analysis suggested that the ZACs interfere negatively with the expression of genes encoding the major components of the A. fumigatus zinc uptake system, thus supporting perturbance of zinc homeostasis as the likely mode of action. With demonstrated in vitro and in vivo antifungal activity, low propensity for resistance development, and a novel mode of action, the ZACs represent a promising new class of antifungal compounds, and their advancement in a drug development program is therefore warranted. American Society for Microbiology 2018-04-26 /pmc/articles/PMC5923171/ /pubmed/29439980 http://dx.doi.org/10.1128/AAC.02024-17 Text en Copyright © 2018 Cohrt et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Mechanisms of Action: Physiological Effects
Cohrt, Karen A. O'Hanlon
Marín, Laura
Kjellerup, Lasse
Clausen, Johannes D.
Dalby-Brown, William
Calera, José Antonio
Winther, Anne-Marie Lund
Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy
title Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy
title_full Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy
title_fullStr Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy
title_full_unstemmed Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy
title_short Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy
title_sort novel zinc-attenuating compounds as potent broad-spectrum antifungal agents with in vitro and in vivo efficacy
topic Mechanisms of Action: Physiological Effects
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923171/
https://www.ncbi.nlm.nih.gov/pubmed/29439980
http://dx.doi.org/10.1128/AAC.02024-17
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