A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism

Abstract

can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to a 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 59,223 small molecules using a resazurin assay that compared their effects on an 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 effects on fungal growth were further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as by toxicity assays on HeLa cells and mice. Six compounds were selected following a rescreening, of which two were pyrazolones, two were porphyrins, and two were polyaminocarboxylates. All three groups showed good 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 fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections by administration of this compound either as a monotherapy or as part of a combination therapy.

Aspergillus fumigatus and Aspergillosis in 2019

“…Importantly, the ZafA-and ZrfC-like proteins are distributed exclusively among fungi, and no orthologs have been found in mammals. Consequently, the ZafA and ZrfC proteins can be considered specific fungal targets, since zinc-chelating compounds can inhibit fungal growth both in vitro and in vivo (372)(373)(374).…”

Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans

“…In the recent years, a successful method to identify novel synergistic drug combinations with current antifungal drugs was through large-scale systematic screens of compound libraries. Several chemical biology screens identified inhibitory drug combinations against S. cerevisiae , S. pombe , C. albicans , Aspergillus fumigatus, and C. neoformans ( 52 – 59 ). For example, Robbins et al, generated an Antifungal Combinations Matrix by evaluating the growth of S. cerevisiae , S. pombe , C. albicans , and C. neoformans in the presence of sub-lethal concentrations of known antifungals (i.e., fluconazole, caspofungin, amphotericin B, terbinafine, benomyl, and cyprodinil) in combination with 3,600 compounds ( 56 ).…”