Building on a landmark 2025 discovery, McMaster researchers have learned how an antibiotic-producing bacterium protects itself from its own chemicals, offering critical insight into how pathogens evolve to resist antibiotics.
The discovery also strengthens the potential for this new antibiotic as a candidate for drug development.
Many bacteria make their own antibiotics, designed to kill or maim competing bacteria, and the vast majority remain immune to the deadly chemicals they produce.
“Over millions of years, evolution has forced a solution,” says Gerry Wright, a professor in the Department of Biochemistry and Biomedical Sciences who led the new study, published Wednesday in the journal ACS Infectious Diseases.
“In order to safely produce these antibiotics, bacteria have evolved complex self-resistance mechanisms that provide them with tailored protection against their own toxic chemicals.”
These custom mechanisms are a window into the evolution of drug resistance and can provide researchers with critical insights into how other bacteria may evolve to resist new drugs, Wright says.
Last year, Wright’s research team discovered a new class of antibiotics called lariocidin, produced by the soil-dwelling bacteria Paenibacillus, a breakthrough detailed in a landmark Nature paper.
The all-new antibiotic, found in soil collected from a Hamilton backyard, is considered to have strong clinical potential, as it attacks a broad range of multidrug-resistant bacteria, is not toxic to human cells, and is not susceptible to known mechanisms of antibiotic resistance.
But if the genes involved in Paenibacillus’ self-resistance to lariocidin are widespread across other bacteria, it could signal potential resistance liabilities for the new drug candidate, Wright says.
“Bacteria are capable of transferring genetic material ‘horizontally,’ from one species or strain to another,” explains Wright, a member of the Michael G. DeGroote Institute for Infectious Disease Research.
“This process allows resistance genes to move between organisms, which can expedite and broaden the spread of antibiotic resistance.”
Wright’s group set out to learn exactly how Paenibacillus’ self-resistance works, so that they could investigate whether other bacteria had similar mechanisms.
The research team found that a single enzyme — called LrcE — is responsible for protecting Paenibacillus from the effects of lariocidin.
“This enzyme adds a small chemical ‘tag’ to lariocidin that prevents the antibiotic from binding to Paenibacillus, offering the bacteria self-resistance,” explains Manoj Jangra, a postdoctoral fellow in Wright’s lab and first author on the new paper.
Researchers did discover close genetic relatives of this enzyme in other bacteria, but they were all identified in environmental species, not human pathogens, Jangra says.
“Together, these findings suggest that lariocidin carries a lower risk of having resistance eventually emerge in the clinic,” he says. “This study strengthens lariocidin’s promise as an attractive candidate for further antibiotic development.”