Lasso-shaped small molecule may be a powerful tool in the fight against infectious diseases

A small molecule shaped like a lasso may be a powerful tool in the fight against infectious diseases, according to a new study in Nature co-authored by University of Illinois Chicago researchers. 

Lariocidin, a peptide made by bacteria living in soil, was effective against several different microbes responsible for deadly infections. UIC researchers working with collaborators at McMaster University in Canada determined how the new antibiotic works and why the drug evades bacterial resistance. 

The holy grail in the field is to find an antibiotic that binds to a new site target, has a novel mechanism of action and has a new structure, compared to antibiotics that have been known before. Lariocidin hits all these goals." 

Alexander Mankin, distinguished professor of pharmaceutical sciences at UIC

The paper was co-authored by UIC postdoctoral researcher Dmitrii Travin and includes UIC co-authors Mankin, Elena Aleksandrova, Dorota Klepacki, Nora Vázquez-Laslop and Yury Polikanov. 

Lariocidin is a newly discovered member of the lasso peptide family – tiny proteins shaped like a lasso, with a loop of amino acids at one end and a tail threaded through it. The new peptide was discovered in bacteria collected in the backyard of one of the scientists in Canada. 

After McMaster researchers observed that lariocidin could kill several disease-causing microbes, they worked with the UIC researchers to study how it works. In biochemical and structural experiments, the team found that lariocidin binds to and blocks the ribosome, the cell's factory for making new proteins. 

"We found a new job for these lasso peptides," Travin said. "No one knew that lasso peptides could bind to the ribosome and kill bacteria by not allowing them to make new proteins." 

Because lariocidin binds at a site different from where other antibiotics bind to ribosomes, it avoids the defenses that bacteria have evolved to resist other drugs. 

"In the antibiotic discovery field, you want a weapon which kills by targeting something different than the previous ones did before," said Polikanov, associate professor of biological sciences. "Otherwise, previously used protections will automatically lead to defense against the new molecule." 

The peptide's unique structure may also help circumvent another common bacterial defense, Travin said. To tie up a ribosome, an antibiotic first needs to get inside the bacterial cell. Many drugs sneak in through transporters, but bacteria can change or remove these to block the drugs. 

By contrast, lariocidin has a strong positive charge, which likely allows it to pass directly through membranes without the need of transporters. That makes the molecule a broad-spectrum antibiotic. 

"If you do not rely on any specific transporter, you can penetrate the majority of bacteria," Travin said. "And if a transporter is not needed, then the probability of resistance is lower." 

The researchers additionally studied a variant of lariocidin, which takes on a more intricate three-dimensional shape, looping its tail to resemble a pretzel. This even more stable structure might be the most promising candidate for clinical development, the researchers said. The bioinformatic analysis of available bacterial genomes suggests there could be other lasso and pretzel peptides that target ribosomes still to be discovered in nature. 

"Essentially, lariocidin is the founding member of a new family of antibiotics with a similar mechanism of action," Travin said. "Time will show whether some other peptides of this kind will be even more active than this one. But we already have our foot in the door." 

Funding for the research was provided by National Institutes of Health to Polikanov, Mankin and Vázquez-Laslop.