Unlocking Iridium Chemical Space for Antibiotic Discovery through One-Pot Combinatorial Synthesis in a Direct-to-Biology Approach.
- 1Department of Chemistry, Biochemistry & Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
- 2Department of Chemistry, University of York, York YO10 5DD, U.K.
- 3Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino 50019, Italy.
Abstract
Antibacterial resistance continues to drive the need for exploring novel chemical spaces beyond conventional organic scaffolds. Metal-based compounds have emerged as a promising class of antibiotic candidates, demonstrating high hit rates against priority bacterial pathogens without exhibiting increased toxicity compared to purely organic molecules. Here, we report a one-pot, three-component combinatorial strategy for the synthesis of piano-stool Ir-(III) cyclopentadienyl Schiff-base complexes as potential antibacterial agents. Using 15 picolinaldehydes (A-O), 24 amines (1-24), and four Cp/Cp* iridium precursors (Cp1-4), a library of 1440 complexes was generated and screened directly from crude reaction mixtures in a direct-to-biology approach. Biological screening revealed pronounced activity against Gram-positive Staphylococcus aureus, particularly for biphenyl-substituted Cp (Cp2) complexes, while no activity was observed against Gram-negative bacteria. A subset of the compounds exhibited potent and selective antibacterial activity with low mammalian cell toxicity. Dose-response validation identified 4 promising hit candidates, of which Ir15 displayed low-micromolar activity against a panel of Gram-positive pathogens, limited hemolysis, and moderate cytotoxicity. Initial mechanistic studies indicate that Ir15 acts through a membrane-associated mode of action involving mild membrane depolarization without large pore formation, alongside changes in nucleoid morphology. Overall, this work establishes Ir-(III)-Cp Schiff-base complexes as a modular antibacterial platform and identifies Ir15 as a promising lead compound for further optimization.
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BibTeX
@article{ozsan2026unlocking,
title = {{Unlocking Iridium Chemical Space for Antibiotic Discovery through One-Pot Combinatorial Synthesis in a Direct-to-Biology Approach.}},
author = {Çağrı Özsan and Athi Welsh and Stefano Zineddu and David R Husbands and Kiera Robinson and Anson Kwok-Hei Chau and Angelo Frei},
journal = {JACS Au},
year = {2026},
month = sep,
doi = {10.1021/jacsau.6c00813},
url = {https://europepmc.org/article/MED/42953627},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Unlocking Iridium Chemical Space for Antibiotic Discovery through One-Pot Combinatorial Synthesis in a Direct-to-Biology Approach.
AU - Çağrı Özsan
AU - Athi Welsh
AU - Stefano Zineddu
AU - David R Husbands
AU - Kiera Robinson
AU - Anson Kwok-Hei Chau
AU - Angelo Frei
PY - 2026
DA - 2026/09/18
JO - JACS Au
DO - 10.1021/jacsau.6c00813
UR - https://europepmc.org/article/MED/42953627
AB - Antibacterial resistance continues to drive the need for exploring novel chemical spaces beyond conventional organic scaffolds. Metal-based compounds have emerged as a promising class of antibiotic candidates, demonstrating high hit rates against priority bacterial pathogens without exhibiting increased toxicity compared to purely organic molecules. Here, we report a one-pot, three-component combinatorial strategy for the synthesis of piano-stool Ir-(III) cyclopentadienyl Schiff-base complexes as potential antibacterial agents. Using 15 picolinaldehydes (A-O), 24 amines (1-24), and four Cp/Cp* iridium precursors (Cp1-4), a library of 1440 complexes was generated and screened directly from crude reaction mixtures in a direct-to-biology approach. Biological screening revealed pronounced activity against Gram-positive Staphylococcus aureus, particularly for biphenyl-substituted Cp (Cp2) complexes, while no activity was observed against Gram-negative bacteria. A subset of the compounds exhibited potent and selective antibacterial activity with low mammalian cell toxicity. Dose-response validation identified 4 promising hit candidates, of which Ir15 displayed low-micromolar activity against a panel of Gram-positive pathogens, limited hemolysis, and moderate cytotoxicity. Initial mechanistic studies indicate that Ir15 acts through a membrane-associated mode of action involving mild membrane depolarization without large pore formation, alongside changes in nucleoid morphology. Overall, this work establishes Ir-(III)-Cp Schiff-base complexes as a modular antibacterial platform and identifies Ir15 as a promising lead compound for further optimization.
SN - 2691-3704
ER -