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

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Metal complexes as antifungals? From a crowd-sourced compound library to first in vivo experiments. / Frei, Angelo; Elliott, Alysha G.; Kan, Alex et al.
In: JACS Au, Vol. 2, No. 10, 24.10.2022, p. 2277–2294.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Frei, A, Elliott, AG, Kan, A, Dinh, H, Braese, S, Bruce, AE, Bruce, MR, Chen, F, Humaidy, D, Jung, N, King, AP, Lye, PG, Maliszewska, HK, Mansour, AM, Matiadis, D, Munoz-Herranz, MP, Pai, T-Y, Pokhrel, S, Sadler, PJ, Sagnou, M, Taylor, M, Wilson, JJ, Woods, D, Zuegg, J, Meyer, W, Cain, AK, Cooper, MA & Blaskovich, MAT 2022, 'Metal complexes as antifungals? From a crowd-sourced compound library to first in vivo experiments', JACS Au, vol. 2, no. 10, pp. 2277–2294. https://doi.org/10.1021/jacsau.2c00308

APA

Frei, A., Elliott, A. G., Kan, A., Dinh, H., Braese, S., Bruce, A. E., Bruce, M. R., Chen, F., Humaidy, D., Jung, N., King, A. P., Lye, P. G., Maliszewska, H. K., Mansour, A. M., Matiadis, D., Munoz-Herranz, M. P., Pai, T-Y., Pokhrel, S., Sadler, P. J., ... Blaskovich, M. A. T. (2022). Metal complexes as antifungals? From a crowd-sourced compound library to first in vivo experiments. JACS Au, 2(10), 2277–2294. https://doi.org/10.1021/jacsau.2c00308

Vancouver

Frei A, Elliott AG, Kan A, Dinh H, Braese S, Bruce AE et al. Metal complexes as antifungals? From a crowd-sourced compound library to first in vivo experiments. JACS Au. 2022 Oct 24;2(10):2277–2294. Epub 2022 Sept 23. doi: 10.1021/jacsau.2c00308

Author

Frei, Angelo ; Elliott, Alysha G. ; Kan, Alex et al. / Metal complexes as antifungals? From a crowd-sourced compound library to first in vivo experiments. In: JACS Au. 2022 ; Vol. 2, No. 10. pp. 2277–2294.

Bibtex

@article{0b5166b0928b44f5ad6f567d893c37f6,
title = "Metal complexes as antifungals?: From a crowd-sourced compound library to first in vivo experiments",
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.",
keywords = "metal complexes, Antifungal, gold, carbenes, antifungal, antimicrobial resistance, antimycotic, organometallic, inorganic",
author = "Angelo Frei and Elliott, {Alysha G.} and Alex Kan and Hue Dinh and Stefan Braese and Bruce, {Alice E.} and Bruce, {Mitchell R.} and Feng Chen and Dhirgam Humaidy and Nicole Jung and King, {A. Paden} and Lye, {Peter G.} and Maliszewska, {Hanna K.} and Mansour, {Ahmed M.} and Dimitris Matiadis and Munoz-Herranz, {Maria Paz} and Tsung-Yu Pai and Shyam Pokhrel and Sadler, {Peter J.} and Marina Sagnou and Michelle Taylor and Wilson, {Justin J.} and Dean Woods and Johannes Zuegg and Wieland Meyer and Cain, {Amy K.} and Cooper, {Matthew A.} and Blaskovich, {Mark A. T.}",
year = "2022",
month = oct,
day = "24",
doi = "10.1021/jacsau.2c00308",
language = "English",
volume = "2",
pages = "2277–2294",
journal = "JACS Au",
issn = "2691-3704",
publisher = "American Chemical Society",
number = "10",

}

RIS

TY - JOUR

T1 - Metal complexes as antifungals?

T2 - From a crowd-sourced compound library to first in vivo experiments

AU - Frei, Angelo

AU - Elliott, Alysha G.

AU - Kan, Alex

AU - Dinh, Hue

AU - Braese, Stefan

AU - Bruce, Alice E.

AU - Bruce, Mitchell R.

AU - Chen, Feng

AU - Humaidy, Dhirgam

AU - Jung, Nicole

AU - King, A. Paden

AU - Lye, Peter G.

AU - Maliszewska, Hanna K.

AU - Mansour, Ahmed M.

AU - Matiadis, Dimitris

AU - Munoz-Herranz, Maria Paz

AU - Pai, Tsung-Yu

AU - Pokhrel, Shyam

AU - Sadler, Peter J.

AU - Sagnou, Marina

AU - Taylor, Michelle

AU - Wilson, Justin J.

AU - Woods, Dean

AU - Zuegg, Johannes

AU - Meyer, Wieland

AU - Cain, Amy K.

AU - Cooper, Matthew A.

AU - Blaskovich, Mark A. T.

PY - 2022/10/24

Y1 - 2022/10/24

N2 - 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.

AB - 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.

KW - metal complexes

KW - Antifungal

KW - gold

KW - carbenes

KW - antifungal

KW - antimicrobial resistance

KW - antimycotic

KW - organometallic

KW - inorganic

U2 - 10.1021/jacsau.2c00308

DO - 10.1021/jacsau.2c00308

M3 - Journal article

VL - 2

SP - 2277

EP - 2294

JO - JACS Au

JF - JACS Au

SN - 2691-3704

IS - 10

ER -