Metal compounds identified as potential new antibiotics, thanks to robots doing ‘click chemistry’
An iridium metal complex has been identified as a promising, albeit unconventional, new antibiotic drug, according to a new study.
The compound is one of more than 600 produced in a study published in December in the journal Natural communications. The researchers used a robot to synthesize the compounds, combining building blocks of metals and organic molecules to generate a huge chemical library in just a week.
Like the the prevalence of drug-resistant bacterial infections is increasingThere is a need for new, effective antibiotics that can kill germs that no longer respond to existing medications. Until now, research has focused on organic, i.e. carbon-based, molecules, leaving metal complexes almost completely unexplored.
These metal-containing compounds differ significantly in shape from their flatter organic alternatives; and their three-dimensional shapes give rise to distinct chemical and biological properties. This attribute, combined with their ease of synthesis, makes these molecules an interesting potential source of future antibiotics, say the study authors.
But because there is little data on the antimicrobial properties of metal complexes, Frei’s team needed an efficient method to quickly make and test as many compounds as possible. Their solution was to merge simple, robust chemistry with cutting-edge automation.
The team began by creating a panel of 192 different ligands, the organic molecules that bind to the metal center and determine the overall final properties of the complex. They did this by using a liquid handling robot to perform “click on chemistry“This robust reaction fuses two types of raw materials – called azides and alkynes – to build nitrogen-containing rings called 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 to generate a total of 672 metal complexes.
“We chose to use liquid handling robots to perform the chemistry because it is simply a matter of combining different reagents in the right ratios,” Frei said. After making the azides, “we then added the alkynes and the catalyst to do the click reaction, and then we used these ligands on different metals. All of this can be done in one pot with robots,” he said.
Each product was analyzed to confirm the formation of the expected complex, then immediately tested for its antibacterial 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.
“This allows us to go from hundreds of compounds to dozens of interesting compounds,” Frei explained.
Complexes containing iridium and rhenium exhibited particularly high levels of antibacterial activity. In total, 59 of the iridium compounds and 61 of the rhenium compounds inhibited the growth of Staphylococcus aureusan important cause of nosocomial infections which can range from mild to deadly. For both metals, toxicity to human cells was variable. From these initial screening results, the team selected the six compounds that most effectively balanced antibacterial activity with low toxicity for further study.
“When we have identified those that are really promising, we can then go back to the bench and redo them, isolate them and characterize them, to confirm what we saw previously with the [unpurified] mixture,” Frei said.
During this second series of tests, one of the iridium complexes clearly stood out. The compound was approximately 50 to 100 times more active against bacteria than toxic to human cells. This large difference is essential to ensure that the complex is both effective in treating an infection and safe to use on human tissue.
Marc Blaskovicha molecular bioscientist from the University of Queensland in Australia who was not involved in the work, was impressed by the effectiveness of Frei’s approach and the diversity of compounds created by the automated synthesis. However, much more needs to be done to turn their antibiotic candidates into viable clinical drugs, he said.
The “most important next steps” are to show that the most promising compounds have drug-like properties, meaning they are chemically stable and don’t have many off-target effects on the body, he told Live Science in an email. Additionally, research needs to demonstrate how these compounds act in a living body, “ideally in reference mouse models of infection,” he said.
In order to gain approval of these potential antibiotics for clinical use, studies in laboratory animals would eventually be followed by clinical trials that could definitively demonstrate that the drugs are both safe and effective for humans.
For now, Frei intends to build on this initial library of compounds, taking advantage of artificial intelligence to help target specific properties.
“We can use this data to make smarter decisions,” he said. “So we can do machine learning and train models to correlate structural features leading to good activity and low toxicity, and then have the model predict for us which compounds we should make next.”
