Novel zinc-attenuating compounds as potent broad-spectrum antifungal agents with in vitro and in vivo efficacy

Autor: Laura Marín, Anne-Marie Lund Winther, Lasse Kjellerup, William Dalby-Brown, José Antonio Calera, Karen A. O'Hanlon Cohrt, Johannes D. Clausen
Přispěvatelé: Innovation Fund Denmark, Pcovery, Consejo Superior de Investigaciones Científicas (España), Universidad de Salamanca, Wellcome Trust, Boehringer Ingelheim Fonds, Ministerio de Economía y Competitividad (España), Kjellerup, Lasse, Lund Winther, Anne-Marie, Kjellerup, Lasse [0000-0002-7855-3567], Lund Winther, Anne-Marie [0000-0002-5776-0989]
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname
Antimicrobial Agents and Chemotherapy
Digital.CSIC. Repositorio Institucional del CSIC
Cohrt, K A OH, Marín, L, Kjellerup, L, Clausen, J D, Dalby-Brown, W, Antonio Calera, J & Winther, A-M L 2018, ' Novel zinc-attenuating compounds as potent broad-spectrum antifungal agents with In Vitro and In Vivo efficacy ', Antimicrobial Agents and Chemotherapy, vol. 62, no. 5, e02024-17 . https://doi.org/10.1128/AAC.02024-17
Popis: 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.
L.K. was supported by Innovation Fund Denmark, DK (4019-00019B). K.A.O.C., J.D.C., L.K., W.D.-B., and A.-M.L.W. are or were employees of Pcovery. L.M. is employed by the Consejo Superior de Investigaciones Científicas (CSIC), and J.A.C. is employed by the Universidad de Salamanca (Spain). Pcovery has filed a patent relating to the compounds described in this publication but does not have any product in development or marketed product related to this publication. There are no other competing interests to declare. Pcovery ApS received funding from Wellcome Trust Research Councils, UK (100480/Z/12), Novo Seeds, DK, and Boehringer Ingelheim Venture Fund, D. J.A.C. thanks the Spanish Ministry of Economy and Competitiveness for financial support through grant SAF2013-48382-R
Databáze: OpenAIRE
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