An artist’s representation of several rod-shaped bacteria colored blue and red with a magnifying glass focusing in on a single bacteria.
Credit: Shutterstock
Scientists found lariocidin—a new antibiotic with a unique mode of action—by growing a soil sample in the lab for a year.
The rise of antimicrobial-resistant pathogens has spurred scientists to search far and wide for new drugs. And while many antimicrobial molecules have been discovered in recent years, it’s rare to find antimicrobials that have entirely new modes of action. Now, scientists have discovered a new antibiotic—a lasso peptide called lariocidin—and it has a distinct mode of action that makes it the first of an entirely new class of antibiotic compound (Nature 2025, DOI: 10.1038/s41586-025-08723-7)
Gerry Wright, a biochemist at McMaster University who led the research, says lariocidin was found in a bacteria called Paenibacillus that was “cultivated from a soil sample that we obtained here in Hamilton from my technician’s backyard.” He says that to find new drugs to combat growing antimicrobial resistance, scientists must “look to more unusual or overlooked sources of antibiotics.” So the team grew the bacteria found in that soil sample for an entire year to let rarer, slower-growing bacteria increase before fractionating the bacteria to look for antimicrobial compounds.
The structure of lariocidin as represented by a series of connected dots labeled with the abbreviations of amino acids.
Credit: Adapted from Nature
Lariocidin is a lasso peptide containing an isopeptide bond at an aspartic acid residue and a tail that extends over and through a central ring structure.
That process led to the group discovering a lasso peptide that exhibited broad-spectrum antibiotic activity and was effective at killing both gram-positive and gram-negative pathogenic bacteria, along with mycobacteria related to those that cause tuberculosis.
Lasso peptides are proteins structured as a ring of amino acids that contains a single isopeptide bond. A tail of amino acids extends out from that bond and threads over the ring’s edge and through the hole in the center. That distinct lasso shape is what the group of peptides was named after. Many lasso peptides show some amount of antimicrobial activity, but lariocidin is unique in that it kills bacteria by binding to the bacterial ribosome.
Lariocidin binds to the aminoacyl site in ribosomes, Wright says. “That's the acceptor site, where the new amino acid containing transfer RNA [tRNA] binds.” And when lariocidin binds to this site, the ribosome can’t read the codons in messenger RNA correctly, thus causing the mistranslation of proteins. That’s a mode of action never before seen in an antimicrobial compound and has Wright hopeful that lariocidin could overcome antimicrobial resistance in a clinical setting.
David Craik, a peptide and protein scientist at the University of Queensland, says: “Irresistible antibiotics have become an illusion, as many antimicrobial peptides, despite showing initial promise, have failed to prevent resistance. However, the proposed dual action of these threaded peptides, targeting the 30S ribosomal subunit and aminoacyl-tRNA, might offer some promise in combating resistance.”
Wright and the team followed up their structural analysis of lariocidin with testing in human cell lines. They found that lariocidin was effective at killing multidrug- and carbapenem-resistant strains of the pathogenic bacteria Acinetobacter baumannii while exhibiting no toxic effects to the human cells. Wright says this lack of toxicity to human cells is because human ribosomes are just different enough from bacterial ribosomes that lariocidin can’t bind to them. The team then infected mice with A. baumannii and found that 100% of the mice treated with lariocidin survived 48 h after treatment, whereas none of the control mice survived that long.
“Despite three decades of research on lasso peptide discovery, this study presents the first report on their in vivo testing,” Craik says. Finding success in a mouse model, he adds, “demonstrates the commercial potential of this class of peptides.”
Wright and colleagues are now exploring how modifying lariocidin might yield other interesting antimicrobial compounds. “I think we've hit a vein of gold in looking for new ribosome-directed antibiotics that are actually quite novel, and we're really excited about it,” he says. But it may still take some time before any of these potential drugs make it into a clinical setting.
Wright says this work wouldn’t have been possible without the “cross-border collaboration between our group and the team at the University of Illinois Chicago.” But disputes between the US and Canada have created an “unnecessary disruption” that complicates future collaboration, he says.
For now, Wright says, the discovery of lariocidin and its mode of action through international collaboration stands as “a great example of how synergistic skills and research funding come together to help solve some of these big problems that we're facing as a society.”
Chemical & Engineering News
ISSN 0009-2347
Copyright © 2025 American Chemical Society
You might also like...