Soil Bacterium Yields Antibiotic with a Never-Before-Targeted Ribosome Site

Scientists at the University of Illinois Chicago have identified a new antibiotic called manikomycin, produced naturally by a soil-dwelling bacterium, that works by targeting the bacterial ribosome in a way no other antibiotic has done before. The findings appear in Nature.

Manikomycin is a peptide made by Streptomyces rimosus, a bacterium that has been known for decades and is already the source of widely used antibiotics, including oxytetracycline. Because Streptomyces rimosus lives in soil and must compete with other microbes to survive, it produces antibiotic compounds as a competitive strategy. Colleagues at McMaster University in Canada used targeted screening methods to search for additional compounds the bacterium produces, including ones present in small amounts that had previously been overlooked.

"It's like this analogy: You serve a dinner, and everyone knows there's this wonderful steak on the plate," said corresponding author Alexander 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."

Like roughly one third of all currently prescribed antibiotics, manikomycin acts on the ribosome—the molecular machine responsible for producing all of a cell's proteins. But where other antibiotics interact with known sites on the ribosome, manikomycin binds to a previously untargeted location. When it does, it blocks an important molecule from exiting the ribosome, halting protein synthesis entirely.

"This new antibiotic is amazing because it targets a site of the ribosome that has never been targeted by any other molecule before," said Dmitrii Travin, first author of the paper. Because the attack site is novel, bacteria "need to jump through hoops to find resistance," Mankin added. 

The researchers also found that manikomycin enters bacterial cells through multiple transport pathways, which may further complicate resistance development. They additionally studied how Streptomyces rimosus protects itself from the antibiotic it produces, knowledge that could help researchers modify the compound to overcome similar resistance strategies.

Manikomycin is not yet ready for clinical use. It does not remain in the bloodstream long enough to effectively kill bacteria in animals or humans. However, researchers now know its chemical structure and exactly how it binds to the ribosome—a high-resolution structure obtained by collaborators at the University of Hamburg—giving them a foundation for future development.