A research team led by Dr. Angelo Frei in the Department of Chemistry at the University of York has demonstrated how robotic synthesis can significantly accelerate the search for new antibiotics. Using an automated chemical platform, the group rapidly produced and screened hundreds of metal-based compounds, identifying several with antibacterial activity. The work addresses a growing concern in medicine as resistance to existing antibiotics continues to rise while the development pipeline for new treatments remains limited.
Husbands, D. R., Özsan, Ç., Welsh, A., Gammons, R. J., & Frei, A. (2025). High-throughput triazole-based combinatorial click chemistry for the synthesis and identification of functional metal complexes. Nature Communications, 16(1), 11195. https://doi.org/10.1038/s41467-025-67341-z
Drug-resistant infections are responsible for more than a million deaths globally each year, and their impact extends beyond infectious disease alone. Many routine medical procedures rely on effective antibiotics to prevent complications, meaning that rising resistance poses risks across healthcare systems. Against this backdrop, Frei’s team explored an area that has received comparatively little attention in modern drug development: metal-based antimicrobial compounds.
Dr. Angelo Frei in the Department of Chemistry at the University of York stated,
“By combining smart ‘click’ chemistry with automation, we have demonstrated that we can explore vast, untapped areas of chemical space at unprecedented speed. We aren’t just looking for one drug; we are proving a methodology that can help us find the ‘needle in the haystack’ much faster.”
Most antibiotics in clinical use today are organic, carbon-based molecules with relatively flat structures. In contrast, metal complexes form three-dimensional architectures that can interact with bacterial cells in different ways. These structural differences may allow such compounds to bypass common resistance mechanisms that limit the effectiveness of existing drugs. While metals have historically been associated with toxicity concerns, recent large-scale screening efforts suggest that certain metal complexes can show antibacterial activity without harming human cells.
To explore this chemical space efficiently, the researchers combined robotics with click chemistry, a method that allows molecular building blocks to be joined quickly and reliably. Nearly 200 ligands were systematically combined with five different metals using an automated system capable of performing hundreds of reactions in parallel. In just under a week, the platform produced more than 700 distinct metal complexes, a scale of synthesis that would normally require months of manual laboratory work.
Each compound was then screened for its ability to inhibit bacterial growth and for its effects on healthy human cells. From this initial screen, six compounds emerged as potential leads. One iridium-based complex showed particularly strong antibacterial performance, including activity against bacteria related to methicillin-resistant Staphylococcus aureus, while maintaining low toxicity in human cell models. This balance between effectiveness and safety indicates a high therapeutic index and supports further investigation.
According to Frei and his colleagues, the significance of the study lies as much in the process as in the individual compounds identified. Antibiotic discovery has slowed in part because traditional screening methods are time-consuming and costly, making them unattractive for large-scale exploration. Automated synthesis and screening provide a way to survey wide regions of chemical space more quickly, increasing the likelihood of finding viable candidates that would otherwise remain undiscovered.
The team is now working to understand how the iridium compound and related complexes exert their antibacterial effects at the molecular level. They also plan to expand the platform to include additional metals and ligand families. Beyond antibiotics, the same robotic approach could be applied to other areas of chemistry, including catalyst discovery and materials development, where large libraries of metal complexes are also of interest
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
