Iridium metal complexes are an unconventional but promising new antibiotic, a new study has found.
The compound is one of more than 600 produced in a study published in Nature Communications in December. The researchers used robots to synthesize compounds, combining building blocks of metal and organic molecules to generate a huge chemical library in just one week.
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As the prevalence of drug-resistant bacterial infections increases, new and effective antibiotics are needed that can kill bacteria that no longer respond to existing drugs. So far, research has focused on organic molecules (meaning carbon-based molecules), and metal complexes are almost completely unexplored.
These metal-containing compounds have very different shapes compared to more planar organic compounds. And its three-dimensional shape creates unique chemical and biological properties. This property and ease of synthesis make these molecules a promising potential source of future antibiotics, the study authors say.
But there is little existing data on the antibacterial properties of metal complexes, so Frei’s team needed an efficient way to quickly create and test as many compounds as possible. Their solution was to combine simple, robust chemistry with cutting-edge automation.
The team started by creating a panel of 192 different ligands, organic molecules that bind to the metal center and determine the final properties of the entire complex. They achieved this by using liquid handling robots to perform “click chemistry.” This powerful reaction fuses two starting materials called azides and alkynes to build nitrogen-containing rings known as triazoles. These nitrogen rings bind strongly to metals.
In the next step of the process, the robot combined each of the 192 ligands with five different metals, producing a total of 672 metal complexes.
“We chose to use a liquid handling robot to perform the chemical reactions because it simply combines different reagents in the right proportions,” Fry said. After creating the azide, he said, “we added an alkyne and a catalyst to perform the click reaction and used those ligands for different metals. All can be done in one pot using a robot.”
Each product was analyzed to confirm that the expected complexes were formed and immediately tested for antimicrobial activity and potential toxicity to human cells. In this way, the team quickly identified the safest and most potent compounds without wasting time on lengthy purification steps.
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“This allows us to go from hundreds of compounds to perhaps dozens of interesting compounds,” Frye explained.
Complexes containing iridium and rhenium showed particularly high levels of antimicrobial activity. Overall, 59 iridium and 61 rhenium compounds inhibited the growth of Staphylococcus aureus, an important cause of mild to fatal hospital infections. Both metals had variable toxicity to human cells. From these initial screening results, the team selected six compounds that most effectively balanced antimicrobial activity and low toxicity for further study.
“Once we identify the really promising ones, we can go back to the bench and rework them, isolate them, characterize them, and confirm what we observed earlier. [unpurified] It’s a mixture,” Frye said.
In this second test, one of the iridium complexes was the clear winner. The compound was approximately 50 to 100 times more active against bacteria than it was toxic to human cells. This significant difference is essential to ensure that this complex is both effective in treating infections and safe for use in human tissue.
Mark Blazkowicz, a molecular bioscientist at the University of Queensland in Australia, who was not involved in the study, was impressed by the efficiency of Fry’s approach and the variety of compounds produced by automated synthesis. However, he said considerable work remains to turn antibiotic candidates into viable clinical drugs.
“The most important next step” is to show that the most promising compounds have drug-like properties, meaning they are chemically stable and do not have many off-target effects in the body, he told LiveScience in an email. Additionally, studies need to demonstrate how these compounds work in vivo, “ideally in a ‘gold standard’ mouse model of infection,” he said.
Approval for clinical use of these potential antibiotics will ultimately require research in laboratory animals followed by clinical trials that can definitively show that the drug is safe and effective in humans.
In the meantime, however, Frei intends to build on this initial library of compounds and leverage artificial intelligence to target specific properties.
“With this data, we can make smarter decisions,” he said. “So we can do machine learning to train a model to correlate which structural features lead to good activity and low toxicity, and have the model predict which compounds to make next.”
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