Metal complexes as antifungals? From a crowd-sourced compound library to first in vivo experiments

Frei, Angelo, Elliott, Alysha G., Kan, Alex, Dinh, Hue, Braese, Stefan, Bruce, Alice E., Bruce, Mitchell R., Chen, Feng, Humaidy, Dhirgam, Jung, Nicole, King, A. Paden, Lye, Peter G., Maliszewska, Hanna K., Mansour, Ahmed M., Matiadis, Dimitris, Munoz-Herranz, Maria Paz ORCID:, Pai, Tsung-Yu, Pokhrel, Shyam, Sadler, Peter J., Sagnou, Marina, Taylor, Michelle, Wilson, Justin J., Woods, Dean, Zuegg, Johannes, Meyer, Wieland, Cain, Amy K., Cooper, Matthew A. and Blaskovich, Mark A. T. (2022) Metal complexes as antifungals? From a crowd-sourced compound library to first in vivo experiments. JACS Au, 2 (10). 2277–2294. ISSN 2691-3704

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There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

Item Type: Article
Additional Information: Acknowledgments: The antimicrobial screening performed by CO-ADD (The Community for Antimicrobial Drug Discovery) was funded by the Wellcome Trust (UK; Strategic Funding Award: 104797/Z/14/Z) and The University of Queensland (Australia; Strategic Funding Award). A.F. thanks the SNF for an Early Postdoc Mobility fellowship (P2ZHP2_177997) that supported his work with CO-ADD. We thank the EPSRC (″Bridging the Gaps Integrate AMR″ grants EP/M027503/1 and EP/P030572/1 to P.J.S.) and China Scholarship Council (studentship for FC). P.J.S.’s research on PGMs is also funded by Anglo American. A.P.K. (Cornell University) thanks the National Institute of Health, National Institute of General Medical Sciences, for a Chemical Biology Interface (CBI) Training Grant (grant T32GM008500). A.K.C. was supported by an Australian Research Council (ARC) DECRA fellowship (DE180100929). S.B. and N.J. acknowledge the DFG Core Facility MOLECULE ARCHIVE (grants BR1750/40-1 and JU2909/5-1) for the management and provision of the compounds for screening and general funding by the DFG (TRR88) and the Helmholtz Association (Biointerfaces). D.W. thanks the Australian Government for an Australian Postgraduate Award Scholarship. Funding by the Faculty of Science at the University of East Anglia is gratefully acknowledged (H.K.M). A.E.B., M.R.B., D.H., and S.P. would like to acknowledge the support from the Department of Chemistry, University of Maine. D.M. was supported by a scholarship co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme ≪Human Resources Development, Education and Lifelong Learning≫ in the context of the project ″Reinforcement of Postdoctoral Researchers-2nd Cycle″ (MIS-5033021) implemented by the State Scholarships Foundation (Ι.Κ.Υ.). We thank Prof. Christiane Grabay and Dr. Rodolphe Alves de Sousa from the Paris Descartes University and the French National Chemical Library for providing compounds for screening ( We acknowledge Compounds Australia ( for their provision of specialized compound management and logistics research services to the project and ACRF and NCRIS for their funding support of the Compounds Australia facility. All cell lines were purchased from the American Type Culture Collection (ATCC).
Uncontrolled Keywords: metal complexes,antifungal,gold,carbenes,antifungal,antimicrobial resistance,antimycotic,organometallic,inorganic,chemistry(all),biochemistry,catalysis,colloid and surface chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1600
Faculty \ School: Faculty of Science > School of Chemistry
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Depositing User: LivePure Connector
Date Deposited: 04 Aug 2022 10:30
Last Modified: 27 Oct 2022 13:41
DOI: 10.1021/jacsau.2c00308

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