Scientists at the University of Illinois Chicago have discovered a new antibiotic that may be a bulwark in the fight against drug-resistant superbugs, according to new research published in Nature.
The study introduces an antibiotic called manikomycin that is naturally made by bacteria found in soil.
Manikomycin acts by binding to the bacteria's ribosome, the molecular machine that makes all the proteins of a cell. This is a common way antibiotics function, said Dmitrii Travin , assistant professor of pharmaceutical sciences in the Retzky College of Pharmacy and a first author of the paper.
"The ribosome is the target of about one third of all antibiotics prescribed currently," he said.
But manikomycin acts on the ribosome in a totally new way.
"This new antibiotic is amazing because it targets a site of the ribosome that has never been targeted by any other molecule before," Travin said.
By attacking the ribosome in a new way, manikomycin can evade the existing mechanisms pathogens have developed to resist antibiotics.
That means "bacteria need to jump through hoops to find resistance," said Alexander Mankin , distinguished professor in the Retzky College of Pharmacy. The paper was co-authored by Mankin and includes UIC co-authors Dorota Klepacki and Nora Vázquez-Laslop.
Familiar target, new attack
Manikomycin is a peptide that is produced naturally by a bacterium called streptomyces rimosus. Because this bacterium lives in soil, it has to compete with many other microbes in its environment. It produces antibiotic compounds like manikomycin as a survival strategy to compete with other bacteria.
Streptomyces rimosus has been known of for decades. It's already the source of other antibiotics, including the widely used oxytetracycline. But Travin and Mankin's colleagues at McMaster University in Canada used clever screening methods to look for possibly other antibiotics also produced by streptomyces rimosus.
That allowed the researchers to find valuable compounds the bacteria made in small amounts but which were overshadowed by more abundant ones.
"It's like this analogy: You serve a dinner, and everyone knows there's this wonderful steak on the plate," said Mankin. "But there is also black caviar, a small quantity in a small dish, which was ignored before because everyone was running after the steak."
When it binds the ribosome, manikomycin interferes with the process of protein production and blocks an important molecule from exiting the ribosome. That halts protein synthesis entirely.
A promising lead
Still, manikomycin is not yet ready to be used as a medicine.
"This antibiotic does not hang around long enough in the bloodstream to efficiently kill bacteria in animals or humans, so there are several things about this antibiotic that need to be improved before it can become a clinically used medicine," Mankin said. "But what's important is we know the chemical structure of the antibiotic, and we know exactly how it binds to the ribosome." The team's collaborators at the University of Hamburg in Germany obtained a high-resolution structure of manikomycin bound with the ribosome.
The researchers have also determined how manikomycin enters bacterial cells. They found that it uses multiple transport pathways — another factor that may make it harder for resistance to develop.
They also examined how the bacteria that produce manikomycin protect themselves from its effects. By understanding that self-protection mechanism, researchers can modify the antibiotic so it can overcome similar resistance strategies.
"If you are producing a weapon, you need to protect yourself against it," Travin said.
Written by Tess Joosse
