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Development of novel, selective antifungal therapies is challenging due to similarities between fungal and mammalian cells. An attractive source of potential antifungal treatments is provided by ecological niches co-inhabited by bacteria, fungi, and multicellular organisms, where complex relationships between multiple organisms have resulted in evolution of a wide variety of selective antimicrobials. Here, we characterized several analogs of one such natural compound, collismycin A. We show that NR-6226C has antifungal activity against several pathogenic\n                    <jats:italic>Candida<\/jats:italic>\n                    species, including\n                    <jats:italic>C. albicans<\/jats:italic>\n                    and\n                    <jats:italic>C. glabrata<\/jats:italic>\n                    , whereas it only has little toxicity against mammalian cells. Mechanistically, NR-6226C selectively chelates iron, which is a limiting factor for pathogenic fungi during infection. As a result, NR-6226C treatment causes severe mitochondrial dysfunction, leading to formation of reactive oxygen species, metabolic reprogramming, and a severe reduction in ATP levels. Using an\n                    <jats:italic>in vivo<\/jats:italic>\n                    model for fungal infections, we show that NR-6226C significantly increases survival of\n                    <jats:italic>Candida<\/jats:italic>\n                    -infected\n                    <jats:italic>Galleria mellonella<\/jats:italic>\n                    larvae. Finally, our data indicate that NR-6226C synergizes strongly with fluconazole in inhibition of\n                    <jats:italic>C. albicans<\/jats:italic>\n                    . Taken together, NR-6226C is a promising antifungal compound that acts by chelating iron and disrupting mitochondrial functions.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Drug-resistant fungal infections are an emerging global threat, and pan-resistance to current antifungal therapies is an increasing problem. Clearly, there is a need for new antifungal drugs. In this study, we characterized a novel antifungal agent, the collismycin analog NR-6226C. NR-6226C has a favorable toxicity profile for human cells, which is essential for further clinical development. We unraveled the mechanism of action of NR-6226C and found that it disrupts iron homeostasis and thereby depletes fungal cells of energy. Importantly, NR-6226C strongly potentiates the antifungal activity of fluconazole, thereby providing inroads for combination therapy that may reduce or prevent azole resistance. Thus, NR-6226C is a promising compound for further development into antifungal treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02594-23","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T09:00:44Z","timestamp":1705482044000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole"],"prefix":"10.1128","volume":"12","author":[{"given":"Jeanne","family":"Corrales","sequence":"first","affiliation":[{"name":"Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Norway"},{"name":"Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway"},{"name":"Section for Biochemistry and Molecular Biology, 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