"An Acetyltransferase Conferring Self-Resistance of the Producer to Lasso Peptide Antibiotic Lariocidin" ACS Infectious Diseases
Early in 2025, scientists discovered a promising new antibiotic in a soil sample from a lab technician's backyard. The molecule, called lariocidin, is produced by the microbe Paenibacillus and shows broad activity against pathogenic bacteria, including several that are multi-drug-resistant. Now, the researchers report in ACS Infectious Diseases how Paenibacillus avoids harm by its own antibiotic - information that is crucial for developing lariocidin or similar compounds into new drug candidates.
Yury Polikanov and Dmitri Travin/University of Illinois, Chicago
"The discovery of a new antibiotic is just the first step in advancing it toward clinical use. It is vital to understand potential mechanisms of resistance to pressure test the novelty and clinical potential of the original discovery," says Gerry Wright, the lead investigator of the lariocidin project.
As bacteria evolve resistance to drugs, new antibiotics are urgently needed. In their initial breakthrough, Wright and colleagues identified that a slow-growing Paenibacillus strain produces lariocidin, which inactivates the bacteria against which it competes for resources in the soil. Expanding on that work, the researchers examined how the microbe resists its own powerful antibiotic.
Lariocidin deactivates bacteria by binding to ribosomal RNA and interfering with protein synthesis. In the current study, the researchers identified one enzyme (shortened to lrcE) produced by the Paenibacillus strain that modifies lariocidin. Their experiments revealed that lrcE adds a functional group onto the antibiotic molecule, which prevents it from binding to the bacterium's ribosomal RNA, thereby protecting Paenibacillus. Additionally, the enzyme was specific to lariocidin and did not impact other antibiotic compounds such as aminoglycosides and streptothricins.
Then, from an analysis of the bacterium's genome, the researchers characterized the gene that encodes the lariocidin-resistance enzyme. A small-scale search for similar genes in environmental bacteria and human pathogens revealed some in Bacillus genomes and environmental proteobacteria but none in the genomes of human pathogens. The researchers say that gene transfer from environmental bacteria to human pathogens is slow and rare, but if lariocidin or related compounds become pharmaceutical treatments, potential gene transfer should be monitored. These insights suggest to the team that lariocidin holds promise as a powerful next-generation antibiotic treatment for humans with minimal risk of resistance, making it a promising candidate for preclinical development.
The authors acknowledge funding from the Canadian Institutes for Health Research, the National Institute of General Medical Sciences of the National Institutes of Health, and Illinois State startup funds.
