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

Frei, Angelo and Elliott, Alysha G. and Kan, Alex and Dinh, Hue and Braese, Stefan and Bruce, Alice E. and Bruce, Mitchell R. and Chen, Feng and Humaidy, Dhirgam and Jung, Nicole and King, A. Paden and Lye, Peter G. and Maliszewska, Hanna K. and Mansour, Ahmed M. and Matiadis, Dimitris and Munoz-Herranz, Maria Paz and Pai, Tsung-Yu and Pokhrel, Shyam and Sadler, Peter J. and Sagnou, Marina and Taylor, Michelle and Wilson, Justin J. and Woods, Dean and Zuegg, Johannes and Meyer, Wieland and Cain, Amy K. and 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

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.