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A team of researchers at the University of Oklahoma has achieved a significant advancement that may transform how we tackle antibiotic-resistant infections, cancer, and other difficult-to-treat gram-negative pathogens, all while moving away from the reliance on precious metals.
At present, elements such as platinum and rhodium play a crucial role in the synthesis of carbohydrates, which are essential building blocks in many approved antibiotics targeting gram-negative pathogens like Pseudomonas aeruginosa. This particular bacterium is notorious for causing infections in hospital settings and is especially deadly for patients with weakened immune systems. The conventional methods of utilizing these precious metals are not only costly but also environmentally damaging, given the harsh conditions required for extraction and processing. In a groundbreaking study published in Nature Communication, the OU team, led by Professor Indrajeet Sharma, has successfully swapped these expensive metals for blue light or iron, achieving comparable outcomes while dramatically minimizing toxicity, lowering costs, and enhancing accessibility for pharmaceutical researchers and manufacturers.
This innovative approach leverages the abundance and affordability of iron and non-toxic blue light to quickly and effectively synthesize critical carbohydrates. Given that many antibiotics depend on carbohydrate structures to breach the protective outer membrane of gram-negative bacteria, this development has the potential to significantly enhance treatment strategies for multi-drug-resistant infections.
“The crisis of drug-resistant infections is a pressing issue that is projected to escalate unless proactive measures are adopted,” stated Sharma. “By employing our techniques for late-stage drug modifications, we can create synthetic carbohydrate-based antibiotics that hold promise for treating these challenging infections. Additionally, carbohydrates can enhance a drug’s solubility, making them suitable for use as pro-drugs that can be administered easily with water.”
A pro-drug refers to a therapeutic agent that is initially inactive but converts to its active form through metabolic processes in the body. Sharma’s team is actively investigating ways to link custom-designed sugars or synthetic sugars to drug molecules to prolong their effectiveness and viability within the human body. They are utilizing a novel blue light-driven technique pioneered by Surya Pratap Singh, a doctoral candidate in Dr. Sharma’s lab, which eliminates the need for metal involvement.
“When a drug molecule degrades too swiftly, it becomes less effective,” Sharma explained. “By substituting an oxygen atom in the carbohydrate with a sulfur atom, the body’s enzymes fail to recognize the modified molecule as a carbohydrate, and therefore, it is not broken down as rapidly. These modified agents, referred to as thiosugars, could significantly improve treatment outcomes for infections as well as various forms of cancer.”
In collaboration with Professor Helen Zgurskaya from OU, the research team is also investigating how their newly developed process could complement ongoing studies on Pseudomonas aeruginosa, a prevalent drug-resistant pathogen typically found in immunocompromised individuals.
“Pseudomonas is a highly resilient infection linked to numerous fatalities among cancer patients,” Zgurskaya noted. “The compounds we have identified in my lab are currently inactive, likely due to their inability to penetrate the pathogen’s outer lipid barrier. By attaching our synthesized carbohydrate molecules to these lead compounds, we aim to enhance their effectiveness against Pseudomonas aeruginosa and similar pathogens. Only time will tell if we achieve this goal.”
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