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

Angelo Frei, Alysha G. Elliott, Alex Kan, Hue Dinh, Stefan Braese, 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, Maria Paz Munoz-Herranz, Tsung-Yu Pai, Shyam Pokhrel, Peter J. Sadler, Marina SagnouMichelle Taylor, Justin J. Wilson, Dean Woods, Johannes Zuegg, Wieland Meyer, Amy K. Cain, Matthew A. Cooper, Mark A. T. Blaskovich

Research output: Contribution to journalArticlepeer-review

Abstract

There are currently fewer than ten antifungal drugs in clinical development, but new fungal strains, which 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 haemolytic properties at similar concentrations. The structures of 21 metal complexes which 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 evaluated for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larvae 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 andchemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.
Original languageEnglish
JournalJACS Au
Publication statusAccepted/In press - 27 Jul 2022

Keywords

  • metal complexes
  • Antifungal
  • gold
  • carbenes

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