Researchers at the University of Oklahoma have made a breakthrough discovery that could potentially revolutionize treatments for antibiotic-resistant infections, cancer and other challenging gram-negative pathogens without relying on precious metals.
Currently, precious metals like platinum and rhodium are used to create synthetic carbohydrates, which are vital components of many approved antibiotics used to combat gram-negative pathogens, including Pseudomonas aeruginosa, a notorious hospital-acquired infection responsible for the deaths of immunocompromised patients. However, these elements require harsh reaction conditions, are expensive to use and are harmful to the environment when mined. In an innovative study published in the journal Nature Communication, an OU team led by Professor Indrajeet Sharma has replaced these precious metals with either blue light or iron, achieving similar results with significantly lower toxicity, reduced costs, and greater appeal for researchers and drug manufacturers.
By using abundant, inexpensive, iron or metal-free, non-toxic blue light, the team can more easily and rapidly synthesize these important carbohydrates. Since most antibiotics rely on a carbohydrate molecule to penetrate the thin, external layer of the gram-negative bacteria, this discovery could transform the way doctors treat multi-drug-resistant pathogens.
"Drug-resistant infections are a major problem and are expected to rise unless something is done," Sharma said. "By using our methods to make late-stage drug modifications, synthetic carbohydrate-based antibiotics could help treat these infections. Furthermore, since carbohydrates can also increase a drug's solubility, they can be easily deployed as a pro-drug that a patient can simply take it with water."
A pro-drug is a medication that it less active when administered and metabolized into its active form. To help drug molecules last longer in the body and work more effectively, Sharma's team is exploring ways to attach specially designed sugars or unnatural sugar to them. They are using a unique blue light-based method, developed by Surya Pratap Singh, a lead researcher and doctoral student in Dr. Sharma's lab, that does not require metals.
"If a drug molecule is broken down too quickly, it loses its potency. 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," Sharma said. "These modified compounds, commonly called thiosugars, could be used to more effectively treat infections and diseases like cancer."
Working with OU professor Helen Zgurskaya, the team is also exploring whether their process can help her research on Pseudomonaa aeruginosa, a widespread, hospital-acquired 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," he 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 her lead compounds, we hope to achieve potency against pathogens like Pseudomonaa aeruginosa. Time will tell."
