Researchers from the UK’s University of York have succeeded in using an advanced robotic system to discover a new drug candidate that could form the core of another generation of antibiotics, providing a new impetus to confront the crisis of bacterial drug resistance, considered one of the most serious global health challenges today. The study, published in the journal Nature Communications, explained how this automated system enabled researchers to produce and test hundreds of chemical compounds in record time, instead of relying on slow traditional methods. The slow traditional methods of discovering and developing antibiotics involve a long and complex series of sequential steps, starting with the manual synthesis of chemical compounds one by one in the laboratory, which is a time-consuming process that requires intense human effort and high precision at each stage. This is followed by purifying each compound individually and then characterizing it chemically using different analytical techniques, before proceeding to biologically test it on specific bacterial strains, often in separate experiments and with limited numbers of samples. Toxicity tests Toxicity tests on human cells are performed gradually and slowly, which limits the number of compounds that can be evaluated during a given period of time. These methods usually rely on traditional carbon molecules with frequent minor changes in the chemical structure, reducing the chances of discovering new mechanisms to overcome bacterial resistance. Due to the lack of automation and parallelism in work, each step depends on the one that preceded it, so that the movement from an initial idea to the identification of a promising compound can take several months or even years, which does not correspond to the acceleration of the antibiotic resistance crisis worldwide. But instead of these methods, the research team relied on a robotic platform capable of creating hundreds of “metal complexes,” which are chemical compounds centered around a metal atom, in a very short period of time. In just one week, researchers were able to produce more than 700 complex metal compounds and then subject them to precise tests to measure their ability to kill bacteria, in addition to their potential toxicity to healthy human cells. This rapid process led to the identification of 6 promising compounds, including a compound based on the metal iridium that emerged as the most striking candidate. High therapeutic index: The iridium-based compound has shown a high ability to eliminate bacteria, including strains close to methicillin-resistant Staphylococcus aureus bacteria, which is one of the most dangerous types of antibiotic-resistant bacteria. The compound showed no significant toxicity towards human cells, meaning it has a high “therapeutic index”, which is an essential feature for any drug candidate for safe and effective use in the future. These results come at a time when experts describe bacterial resistance to drugs as a “silent pandemic”, as it is estimated that more than a million people die each year from infections that could be prevented but have become untreatable due to the failure of current antibiotics. Bacterial resistance to antibiotics Antibiotic resistance is one of the most serious threats to global health, affecting food security and development, and threatening the benefits of modern medicine. Anyone can be affected by antibiotic resistance, regardless of age or country, as it is a global problem that crosses borders. Resistance occurs naturally, but misuse and overuse of antibiotics in humans and animals dangerously accelerates their spread. Many common infections have become difficult or impossible to treat, such as pneumonia, tuberculosis, septicemia and gonorrhea, due to the reduced effectiveness of available antibiotics. It is bacteria that develop resistance, not humans or animals, which leads to more severe infections that are difficult to treat and persist for longer periods of time. Antibiotic resistance increases the length of hospital stay, increases medical costs and leads to higher mortality rates. The indiscriminate purchase of antibiotics without a prescription, and poor adherence to treatment guidelines, are among the most prominent reasons for the worsening of the problem worldwide. The world is at risk of entering the “post-antibiotic era”, and simple infections and common infections can turn deadly again if urgent action is not taken. Prevention is the cornerstone of combating resistance, and includes improving hygiene, vaccination, rational use of antibiotics and reducing the spread of infection in the community, hospitals and agriculture. Even if new antibiotics are developed, resistance will remain a threat unless usage behavior changes and efforts are coordinated between individuals, health professionals, policy makers, industry and agriculture at the global level. Scientists have warned that if new drugs are not developed, routine medical procedures such as hip replacement, chemotherapy or organ transplantation could turn into high-risk operations due to the possibility of developing uncontrollable infections. This work was led by a research team led by Dr Angelo Frei from the Department of Chemistry at the University of York, who together with his colleagues chose to turn to an area that had been marginalized for a long time in drug development, which is the field of metal-based compounds. Click chemistry: Unlike most modern antibiotics, which consist of relatively flat carbon molecules, metal complexes have a three-dimensional structure, which gives them different ways to interact with bacterial cells and may allow them to bypass resistance mechanisms that bacteria have developed against conventional drugs. To achieve this progress, the team used a combination of robotics and chemistry known as “click chemistry,” a method that allows different molecular components to be attached quickly and efficiently, much like putting pieces together with nails. Using this automated platform, the researchers combined almost 200 different types of ligands – the molecules that surround the metal in the complex – with five different metals. The result was a vast library of new compounds, produced in less than a week, a task that would have required several months of manual work in traditional laboratories. After the synthesis phase, all compounds underwent rigorous testing to measure their antibacterial efficacy, as well as their safety on human cells. Among hundreds of compounds, six new candidates emerged, before iridium topped the list thanks to its striking combination of high potency and low toxicity. Angelo Fry said that the line of developing new antibiotics has been suffering from a drought for decades, noting that traditional screening methods are very slow, and that large pharmaceutical companies have largely withdrawn from this field due to poor economic returns. Fry added that the combination of smart click chemistry and automation has enabled researchers to explore vast, unprecedented areas of “chemical space” at unprecedented speed, explaining that the achievement is not limited to the discovery of a single promising compound, but rather is the demonstration of a new methodology that can accelerate finding “the needle in the haystack”. Misconception Although metal-based drugs have historically been considered inherently toxic, data from the Open Society for Antimicrobial Drug Discovery initiative suggest that metal complexes may actually have a higher success rate in eliminating bacteria without causing toxicity than traditional organic molecules. The team from the University of York hope that their results will help to re-engage the interest of the scientific community and pharmaceutical companies in this field. Researchers are currently working to understand the exact mechanism used by the iridium compound to attack bacteria, in addition to expanding the capabilities of their robotic platform to test other metals, in a move that could open the door to a new generation of antibiotics capable of confronting one of the most serious health threats of the modern era.
