Scientists use relay synthesis to create key building blocks of reserve antibiotic to combat resistance

Scientists from Otto von Guericke University Magdeburg have made a breakthrough in the development of potential new antibiotics by successfully synthesizing key structural elements of Neosorangicin A, a compound showing promise in combating drug-resistant bacteria. The research, led by Professor Dr. Dieter Schinzer from the Institute of Chemistry, marks a significant advancement in the field of medicinal chemistry and offers a pathway toward creating more effective treatments for infections caused by resistant strains. The team employed a technique known as relay synthesis to construct essential parts of Neosorangicin A. Rather than attempting to synthesize the entire molecule in one go, the researchers focused on assembling smaller, critical segments that act as stepping stones toward the final product. This method allowed them to address the complexity of the molecule while maintaining precision in its structure. Their findings were recently published in Chemistry, A European Journal, highlighting the scientific innovation behind the process. Neosorangicin A is a secondary metabolite produced by myxobacteria, a group of soil-dwelling microbes known for their ability to generate bioactive compounds. These substances often serve as tools in microbial competition, helping the producers gain an advantage over other organisms. In laboratory studies, Neosorangicin A has demonstrated the ability to inhibit bacterial RNA polymerase, an enzyme crucial for transcription, the process through which bacteria convert genetic information into proteins necessary for growth and reproduction. This mechanism makes Neosorangicin A particularly effective against gram-negative bacteria, a category of pathogens that pose significant challenges in clinical settings. Gram-negative bacteria are shielded by an outer membrane that prevents many conventional antibiotics from reaching their targets. As a result, these microbes are responsible for numerous hospital-acquired infections and are increasingly difficult to treat due to their resistance to existing drugs. Professor Schinzer emphasized the biological significance of Neosorangicin A, noting that its structure presents considerable challenges for synthetic chemists. The molecule features 16 chiral centers, points where the spatial orientation of atoms must be exact to ensure proper interaction with target proteins. Any deviation in these positions could render the compound ineffective or even harmful. Additionally, the compound's instability in biological environments complicates efforts to develop it into a viable pharmaceutical agent. To overcome these obstacles, Schinzer’s team devised a convergent synthesis strategy. They divided the molecule into three distinct, highly complex subunits, each requiring up to 19 chemical steps to produce. These fragments were then joined together using specialized coupling reactions to form the complete carbon framework of Neosorangicin A. This approach enabled greater control over the synthesis process and minimized the risk of errors during assembly. Antibiotic resistance is a growing public health crisis, recognized by the World Health Organization as one of the most pressing threats to human health globally. According to a recent study published in The Lancet in 2024, approximately 1.14 million deaths in 2021 were directly attributed to bacterial resistance, with another 4.71 million linked indirectly. Projections suggest that by 2050, up to 1.91 million people could die annually due to infections caused by resistant pathogens. The successful synthesis of Neosorangicin A opens new avenues for modifying the compound to enhance its stability and efficacy. By altering specific parts of the molecule, researchers aim to improve its pharmacological properties, making it more suitable for therapeutic applications. Such modifications could lead to the development of novel antibiotics capable of addressing current gaps in treatment options. The work conducted by Schinzer and his colleagues represents a critical milestone in the search for alternative antimicrobial agents. It provides a foundation upon which future research can build, potentially leading to the creation of new drugs that can combat the rising tide of antibiotic resistance. Researchers are now focusing on refining the synthetic methods and exploring ways to optimize the compound for clinical use.