A collaboration between researchers at the University of Illinois Chicago (UIC) and Harvard University has resulted in the development of a new, promising antibiotic that effectively suppresses pathogenic bacteria that have become treatment-resistant.
Details of the new antibiotic are published in the journal Science.
The novel antibiotic is the latest fruit of a longtime researcher partnership between UIC researcher Yury Polikanov, PhD, and researchers at Harvard. In this case, investigators from UIC provided information on cellular mechanisms and structure that aided the Harvard team to synthesize the new drug.
The research that led to the development of the novel antibiotic was focused on how antibiotics interact with the ribosome—a common cellular target—and how drug-resistant bacteria modify their ribosomes in order to survive. Ribosomes are the catalyst within cells for the biosynthesis of proteins. Antibiotics bind to bacterial ribosomes thereby disrupting protein synthesis eventually causing the bacteria to die.
But bacteria are also known to evolve to provide a defense against targeting their ribosomes. One defense adds a single methyl group of one carbon and three hydrogen atoms which interferes with the ability of antibiotics to bind to the ribosomes. Previously, researchers had speculated that the bacteria simply blocked the binding sit on the ribosome “like pushing a pin into a chair,” noted Polikanov, an associate professor of biology at UIC.
But to better understand the activity of drug-resistant ribosomes, the investigators turned to X-ray crystallography to get a highly detailed look at how ribosomes fend off antibiotics. Their work found two defensives: the methyl group physically blocks the binding site, but it also changes the shape of the inner portions of the ribosome to further thwart the activity of antibiotics.
Using this information, the team again employed X-ray crystallography to find how certain drugs are able to circumvent this form of 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 the available structural data or by computer modeling,” Polikanov said. “It’s always better to see it once than hear about it 1,000 times, and our structures were important for designing this promising new antibiotic and understanding how it manages to escape the most common types of resistance.”
This resulted in the creation of a new synthetic antibiotic called cresomycin, which has been designed to avoid the common methyl-group interference and bind strongly to ribosomes to disrupt their function. The design of the drug relied on locking the drug into a specific shape that would help it evade bacterial defenses.
“It simply binds to the ribosomes and acts as if it doesn’t care whether there was this methylation or not,” Polikanov said. “It overcomes several of the most common types of drug resistance easily.”
The drug was tested in animal models and showed it protected against infection with multi-drug resistant bacterial strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The next step will be to move cresomycin into clinical studies in humans to test its safety and efficacy.
