Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First In Vivo Experiments
Year: 2022
Type: article
Abstract: 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.
Source: JACS Au
Authors: Angelo Frei, Alysha G. Elliott, Alex Kan, Hue Dinh, Stefan Bräse, Alice E. Bruce, Mitchell R. Bruce, Feng Chen, Dhirgam Humaidy, Nicole Jung, A. Paden King, Peter G. Lye, Hanna K. Maliszewska, Ahmed M. Mansour, Dimitris Matiadis, María Paz Muñoz, Tsung-Yu Pai, Shyam Pokhrel, Peter J. Sadler, Marina Sagnou, Michelle Taylor, Justin J. Wilson, Dean Woods, Johannes Zuegg, Wieland Meyer, Amy K. Cain, Matthew A. Cooper, Mark A. T. Blaskovich
Institutions: University of Bern, The University of Queensland, Institute for Molecular Bioscience, The University of Sydney, Westmead Hospital, Westmead Institute for Medical Research, ARC Centre of Excellence in Synthetic Biology, Macquarie University, Karlsruhe Institute of Technology, University of Maine, University of Warwick, Cornell University, University of New England, University of East Anglia, Norwich Research Park, Cairo University, National Centre of Scientific Research "Demokritos", Institute of Biosciences & Applications
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,067
Funders: Wellcome Trust, University of Maine, Australian Government, University of East Anglia, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, State Scholarships Foundation, China Scholarship Council, Helmholtz Association, Engineering and Physical Sciences Research Council, Australian Research Council, National Institute of General Medical Sciences, European Social Fund
Awards: G1483928380, Multi-User Equipment to Refresh Underpinning Analytical Capabilities at the University of Warwick, Community for Open Antimicrobial Drug Discovery (CO-ADD), A neglected silver bullet? Metal-complex based approaches against antimicrobial resistance, G1990791120, G2043059915, G2370571295, G2892642490, G3077243175, G3742124987, Stronger together: understanding antibiotic synergy on a molecular level, Cross-scale prediction of Antimicrobial Resistance: from molecules to populations., G8077336269
OpenAlex ID: W4296828026