A new class of antibiotics that binds to ribosome and disrupts protein synthesis could be the next tool targeting the growing threat of drug resistant bacteria.
An international team led by researchers from the University of Illinois at Chicago and Nosopharm, a biotechnology company based in Lyon, France, discovered that symbiotic bacteria, found in soil-dwelling nematode worms that colonize insects for food produce, an antibiotic called odilorhabdins (ODLs).
The bacteria helps to kill the insect, while secreting the antibiotic to keep competing bacteria away.
The researchers screened 80 cultured strains of the bacteria for antimicrobial activity and then isolated the active compounds and studied their chemical structures. They then engineered derivatives that are more potent.
The team found that ODLs act on the ribosome—the molecular machine of individual cells that make the protein needed to function—of bacterial cells.
“Like many clinically useful antibiotics, ODLs work by targeting the ribosome, but ODLs are unique because they bind to a place on the ribosome that has never been used by other known antibiotics,” Yury Polikanov, an assistant professor of biological sciences in the UIC College of Liberal Arts and Sciences, said in a statement.
The team also found that when bound to the ribosome, the antibiotic disrupts its ability to interpret and translate genetic code.
“When ODLs are introduced to the bacterial cells, they impact the reading ability of the ribosome and cause the ribosome to make mistakes when it creates new proteins,” Alexander Mankin, director of the Center for Biomolecular Sciences in the UIC College of Pharmacy, said in a statement. “This miscoding corrupts the cell with flawed proteins and causes the bacterial cell to die.”
During the study, ODL compounds cured mice infected with several pathogenic bacteria and demonstrated activity against both Gram-negative and Gram-positive pathogens, including Carbapenem-resistant Enterobacteriacae, a family of germs that have high levels of resistance to antibiotics and are common in bloodstream and surgical site infections, contributing to death in up to 50 percent of patients who become infected.
The antibiotic could be effective at treating both drug-resistant and hard-to-treat bacterial infections.
“The bactericidal mechanism of ODLs and the fact that they bind to a site on the ribosome not exploited by any known antibiotic are very strong indicators that ODLs have the potential to treat infections that are unresponsive to other antibiotics,” Mankin said.
According to the World Health Organization, antibiotic resistant is one of the biggest threats to global health today and a significant contributor to longer hospital stays, higher medical costs and increased mortality.
The study was published in Molecular Cell.
Filed Under: Drug Discovery
