New peptide antibiotic stops bacteria by binding where no drug has before

Lariocidin hits drug-resistant bacteria where others fail — by hijacking the ribosome at a new site, bypassing defences, and opening the door to a new generation of antibiotics.

Lariocidin, a lasso-shaped peptide with promising antibiotic properties. (Graphic: Dmitrii Travin and Yury Polikanov). Research: A broad-spectrum lasso peptide antibiotic targeting the bacterial ribosome

Researchers at McMaster University, in collaboration with researchers from the University of Illinois at Chicago, have discovered a powerful candidate antibiotic that can kill a broad range of bacteria, including those resistant to existing antibiotics. They have published the findings in the journal Nature.

Background

Antibiotic resistance occurs when bacteria evolve and develop resistance against existing antibiotics. It is a major public health crisis worldwide that makes the treatment of bacterial infections challenging. More than 4.5 million deaths occurred due to antibiotic resistance in 2019.

The World Health Organization (WHO) has designated Gram-negative bacteria as a critical threat because of their ability to develop and spread antibiotic resistance, making it a top priority to discover novel antibacterial drugs.

Various peptide-based antibiotics produced by microbes have shown high efficacy in treating bacterial infections. Most of these antibiotics are produced outside the ribosome, the cellular structure responsible for protein synthesis, by specialized peptide synthetases encoded in the genomes of antibiotic-producing microbes.

Ribosomally synthesized and post-translationally modified peptides are rapidly gaining popularity as a novel class of antibiotics. The post-translational modifications set the three-dimensional shape of these peptides, facilitating their interactions with the target proteins and protecting them from degradation by cellular peptidases.

Lasso peptides are biologically active molecules with a distinct, structurally constrained knotted fold that belong to the class of ribosomally synthesized and post-translationally modified peptides. Lasso peptides act on several bacterial targets; however, none of them has been identified as targeting the bacterial ribosome.

In this Nature article, Professor Gerry Wright from McMaster University and his team reported the identification of a new lasso peptide named lariocidin that acts as a broad-spectrum antibiotic by targeting the bacterial ribosome at a unique site.

Importantly, lariocidin not only inhibits protein synthesis by interfering with translocation but also induces translation errors (miscoding), giving it a dual mechanism of action.

The researchers note that lariocidin meets three key criteria for a next-generation antibiotic: a novel structure, a new binding site, and a distinct mechanism of action.

The study

Researchers generated a collection of environmental bacterial strains by culturing them in the laboratory for approximately one year. Such a long-term culture allowed the growth of even the slowest-growing bacteria that could have otherwise been missed.

They prepared methanolic extracts of individual bacterial colonies and tested them against a multidrug-resistant bacterium. This led to the identification of a novel lasso peptide, lariocidin, which was produced by a type of soil bacterium called Paenibacillus.

By conducting a series of biochemical and structural experiments, they found that lariocidin is capable of killing a wide range of bacteria, including multidrug-resistant strains, by inhibiting ribosomal protein synthesis.

They also found that lariocidin binds to a unique site in the small ribosomal subunit of bacteria, which is clearly distinct from the sites of action of existing antibiotics that target the small ribosomal subunit. This unique binding site enabled lariocidin to circumvent the defense mechanisms that bacteria have evolved to resist other drugs.

This ribosomal binding mode relies primarily on interactions with the RNA backbone rather than the nucleobases, making it less susceptible to resistance caused by mutations at the binding site.

In lab-adapted bacterial strains with a single ribosomal RNA operon, researchers identified rare spontaneous mutations in the 16S rRNA that reduced lariocidin susceptibility—further validating the ribosome as its target.

The team emphasized that developing antibiotics that act at previously untapped ribosomal sites offers a way to bypass common resistance mechanisms.

As observed by researchers, the unique structure of lariocidin enabled it to overcome the challenges that other antibiotics typically face when targeting the bacterial ribosome. Mechanistically, antibiotics initially enter the bacterial cell through transporters in order to inhibit protein synthesis, specifically the ribosome. However, bacteria can change or remove these transporters to block the entry of antibiotics.

The strong positive charge of lariocidin, on the other hand, enabled it to enter the bacterial cell directly through the membrane without the need for transporters. This specific feature made lariocidin a broad-spectrum antibiotic.

Because lariocidin bypasses the need for specific transporters, it can enter a wide range of bacterial species, reducing the likelihood of resistance developing through transporter-related mechanisms.

Using a mouse model of Acinetobacter baumannii infection, researchers demonstrated that lariocidin is capable of significantly reducing the bacterial burden in various organs. They further found that the peptide has a low propensity for generating spontaneous resistance and has no cytotoxic effects on human cells.

Its antimicrobial activity was even stronger in nutrient-limited media that mimic host environments, suggesting improved clinical potential compared to standard susceptibility tests in rich media.

This enhanced potency was linked in part to the presence of bicarbonate, which increases bacterial membrane potential and promotes uptake of the positively charged lariocidin.

All these features made lariocidin a promising candidate for further development into a clinical antibiotic for the treatment of serious bacterial multidrug-resistant infections.

The study also identified a structurally related isoform, lariocidin B (LAR-B), which contains an additional isopeptide bond, forming a double-lariat structure. This may improve the stability of the molecule and marks LAR-B as the founder of a proposed new class (class V) of lasso peptides.

By conducting bioinformatic analysis of available bacterial genomes, researchers suggested that there could be other ribosome-targeting lasso peptides still to be discovered in nature.

They identified dozens of lariocidin-like biosynthetic gene clusters (BGCs) across multiple bacterial phyla, including Actinomycetota, Bacilliota, and Proteobacteria, suggesting a wide evolutionary distribution of this antibiotic scaffold.

The researchers describe lariocidin as the first member of a previously unrecognized family of ribosome-targeting lasso peptides, with the potential for even more potent analogs to be discovered.

The researchers are now working on developing strategies to modify the lasso peptide and produce it in large quantities for clinical development.

• Jangra, M., Travin, D. Y., Aleksandrova, E. V., Kaur, M., Darwish, L., Koteva, K., Klepacki, D., Wang, W., Tiffany, M., Sokaribo, A., Coombes, B. K., Polikanov, Y. S., Mankin, A. S., & Wright, G. D. (2025). A broad-spectrum lasso peptide antibiotic targeting the bacterial ribosome. Nature, 1-9. DOI: 10.1038/s41586-025-08723-7, https://www.nature.com/articles/s41586-025-08723-7