Antibiotic resistance is steadily eroding one of modern medicine’s most essential tools. Each year, more than a million people lose their lives to infections that were once easily treatable, a reminder that our current drugs are no longer keeping pace with evolving bacteria. Without new antibiotics, everyday medical procedures—from joint replacements to cancer therapies—carry a growing risk of infections that may no longer respond to treatment. The need for fresh solutions isn’t hypothetical; it’s a practical requirement for maintaining the safety of routine healthcare.
To combat drug-resistant infections, researchers from the University of York, led by Angelo Frei, PhD, have turned to metal-based compounds for answers. Using a cutting-edge robotic system capable of synthesizing hundreds of metal complexes, they hoped to develop a screening method for metal-based antibiotic candidates. In a study published in Nature Communications titled “High-throughput triazole-based combinatorial click chemistry for the synthesis and identification of functional metal complexes,” their rapid screening process identified an iridium-based antibiotic candidate that shows promise in human cells to kill bacteria while remaining nontoxic.
“The pipeline for new antibiotics has been running dry for decades. Traditional screening methods are slow and the pharmaceutical industry has largely withdrawn from this space due to low returns on investment. We have to think differently,” said Frei.
This high-throughput combinatorial approach uses copper(I)-catalyzed alkyne–azide cycloaddition chemistry to make triazole ligands. Although most modern carbon-based antibiotic molecules are “flat,” these metal complexes are three-dimensional, allowing them to interact with bacteria in completely different ways that could potentially overcome the resistance mechanisms.
The Frei lab used robotics and a method where two molecular compounds are bolted together, called “click” chemistry. “This ligand library is coordinated to five metal scaffolds under mild conditions to yield 672 metal compounds, allowing for the accelerated exploration of the transition metal complex chemical space,” wrote the authors. David Husbands, PhD, a postdoctoral researcher in the Frei lab, used this automated platform to combine almost 200 triazole ligands.
The team then screened these compounds for both antibacterial activity and toxicity in human embryonic kidney cells (HEK293T), identifying six promising metalloantibiotics. After a transfer hydrogenation screening assay and resynthesis, one iridium-based compound showed high effectiveness against bacteria with low toxicity.
“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. The iridium compound we discovered is exciting, but the real breakthrough is the speed at which we found it. This approach could be the key to avoiding a future where routine infections become fatal again,” added Frei.
While metal-based compounds have held a reputation of being inherently toxic, new data puts this long-held assumption into question. With hopes that this new methodology will encourage the wider scientific community and pharmaceutical companies to revisit metal complexes, the team’s next steps are to understand how the iridium compound kills bacteria, with plans to expand their platform to test other metals.
