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Researchers at Harvard University and the University of Illinois at Chicago have created an antibiotic that could provide a new tool in the fight against drug-resistant bacteria and the diseases they cause.
According to science, the antibiotic Cresomycin efficiently kills pathogenic microorganisms that have developed resistance to a variety of frequently administered antimicrobial drugs.
The promising new antibiotic is the result of a long-term collaboration between the laboratory of Yuri Polikanov at UIC, an associate professor of biological sciences, and colleagues at Harvard. Harvard researchers use the important insights into cellular function and structure that UIC scientists provide to aid in the design and synthesis of new medicines.
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In developing the new antibiotic, the group focused on how many antibiotics interact with a common cellular target – the ribosome – and how drug-resistant bacteria modify their ribosomes to protect themselves.
More than half of the antibiotics inhibit the growth of pathogenic bacteria by interfering with their protein biosynthesis — a complex process catalyzed by ribosomes, which is similar to “a 3D printer that makes all the proteins in a cell,” Polikanov said. Antibiotics bind to bacterial ribosomes and disrupt this protein-making process, causing the bacterial invaders to die.
But many bacterial species have evolved simple defenses against this attack. In one defense, they interfere with antibiotic activity by adding a methyl group of one carbon and three hydrogen atoms to their ribosomes.
Scientists speculated that this defense was simply a matter of the bacteria physically blocking the spot where the drugs bind to the ribosome, “like putting a push pin on a chair,” Polikanov said. But researchers found a more complicated story, as they described in a paper published last month in Nature Chemical Biology.
Using a method called X-ray crystallography to visualize drug-resistant ribosomes with almost atomic precision, they discovered two defensive strategies. They found that the methyl group physically blocks the binding site, but it also changes the shape of the internal “gut” of the ribosome, disrupting antibiotic activity.
Polikanov’s lab then used X-ray crystallography to investigate how certain drugs, including one published in Nature by the UIC/Harvard collaboration in 2021, prevent this common form of bacterial resistance.
“By determining the actual structure of antibiotics interacting with two types of drug-resistant ribosomes, we saw what could not have been predicted by available structural data or computer modeling,” Polikanov said.
“It’s always better to see it once than hear about it 1,000 times, and our structures were key to designing this promising new antibiotic and understanding how it evades the most common types of resistance.”
Crasomycin, the new antibiotic, is synthetic. It is prearranged to avoid methyl-group interference and bind tightly to ribosomes, disrupting their function. This process involves locking the drug into a shape that is pre-adapted to bind to ribosomes, which helps protect against bacteria.
“It just binds to the ribosome and acts like it doesn’t care whether it was methylated or not,” Polikanov said. “It easily overcomes many of the most common types of drug resistance.”
In animal experiments conducted at Harvard, the drug protected against infection with multidrug-resistant strains of common disease drivers, including Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Based on these promising results, the next step is to assess the effectiveness and safety of cresomycin in humans.
But even at this early stage, according to Polikanov, the process shows the important role of structural biology in designing the next generation of antibiotics and other life-saving drugs.
“Without the structures, we would be blind to how these drugs bind and act on the modified drug-resistant ribosomes,” Polikanov said.
“The structures we determined provide fundamental insight into the molecular mechanisms that allow these drugs to escape resistance.”
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