Currently, precious metals like platinum (Pt) and rhodium (Rh) are required to synthesize the carbohydrates used in the development of many antibiotics. A light-driven alternative to precious metals, and another alternative using an abundant earth element, could make the creation of synthetic carbohydrates more cost-effective and sustainable, transforming antibiotic treatments for infections and cancer. Discovered by a research team at the University of Oklahoma (OU), the new strategy allows precious metals to be replaced with either photosensitizer-free blue light or iron (Fe) during the process of synthesizing carbohydrates. In experiments, this strategy led to results comparable to those achieved using precious metals, with significantly lower toxicity and reduced costs. The new approach offers researchers and drug manufacturers an eco-friendly alternative to traditional methods of catalytic glycosylation, a crucial step in the development of many antibiotics. The researchers found that photosensitizer-free blue-light-promoted carbenes or Fe could be used to activate thioglycosides via intramolecular pathways, enabling the development of orthogonal and stereoselective glycosylation strategies under mild conditions. The mild, carbene-based activation was found to provide orthogonal reactivity similar to traditional glycosyl donors. The proximity-driven, intramolecular design was able to accommodate a range of nucleophiles. University of Oklahoma professor Indrajeet Sharma and his team are using blue light and iron (Fe) instead of precious metals to create synthetic carbohydrates, which are vital components of many antibiotics used to combat gram-negative pathogens. Courtesy of the University of Oklahoma. Precious metals require harsh reaction conditions, are expensive, and are harmful to the environment when mined. By substituting blue light or Fe for precious metals, pharmaceutical manufacturers will be able to synthesize carbohydrates for new antibiotics faster, more safely, and at lower cost. Most antibiotics rely on a carbohydrate molecule to penetrate the external layer of gram-negative bacteria, making this discovery especially relevant for the treatment of multi-drug-resistant pathogens. “Drug-resistant infections are a major problem and are expected to rise unless something is done,” professor Indrajeet Sharma, who led the research, said. “By using our methods to make late-stage drug modifications, synthetic carbohydrate-based antibiotics could help treat these infections.” Since carbohydrates can increase a drug’s solubility, they could be deployed as a pro-drug — a medication that is metabolized into its active form — that a patient takes with water. To help drug molecules last longer in the body and work more effectively, the team is exploring ways to use blue light to attach specially-designed sugars to the molecules. “If a drug molecule is broken down too quickly, it loses its potency,” Sharma said. “By replacing an oxygen atom in the carbohydrate molecule with a sulfur one, enzymes in the human body won’t recognize the molecule as a carbohydrate and won’t break it down as quickly. These modified compounds, commonly called thiosugars, could be used to more effectively treat infections and diseases like cancer.” The blue-light-based method for extending drug efficacy does not involve the use of metals. Sharma and his team are also working with OU professor Helen Zgurskaya to investigate whether their process for synthesizing carbohydrate molecules is applicable to Zgurskaya’s research on Pseudomonas aeruginosa, a drug-resistant pathogen commonly found in immunocompromised patients. “Pseudomonas is a very persistent infection that is responsible for a large number of deaths in cancer patients,” Sharma said. "Currently, compounds identified in the Zgurskaya lab for Pseudomonas are inactive. We believe this is because they cannot cross the thin outer lipid layer of the gram-negative pathogen. By attaching our synthesized carbohydrate molecule to the lab’s lead compounds, we hope to achieve potency against pathogens like Pseudomonas aeruginosa. Time will tell.” The new approach to synthesizing carbohydrates for antibiotic drugs could advance the field of glycosylation and set the stage for further development of sustainable methods in carbohydrate chemistry. The broad applicability and potential to use the approach for late-stage functionalization could make this method a valuable tool for both fundamental research and practical applications in the synthesis of complex glycoconjugates. The research was published in Nature Communications (www.doi.org/10.1038/s41467-025-56445-1).