A novel polyaminocarboxylate compound to treat murine pulmonary aspergillosis by interfering with zinc metabolism [PublishAheadOfPrint]

Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to the lack of reliable treatment options. This opportunistic pathogen requires zinc in order to grow and cause disease. Novel compounds that interfere with fungal zinc metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59223 small molecules using a resazurin assay that compared their effects on an A. fumigatus wild type strain grown under zinc-limiting conditions and on a zinc transporter knockout strain grown under zinc-replete conditions to identify compounds affecting zinc metabolism. After a first screen 116 molecules were selected whose inhibitory effect on fungal growth was further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as to toxicity assays on HeLa cells and mice. Six compounds were selected following a re-screening, two of which were pyrazolones, two were porphyrins and two were polyaminocarboxylates. All three groups showed good in vitro activity but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with in vivo fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections either by administration of this compound as a monotherapy or as part of a combination therapy.

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