Princeton Engineering researchers report they have isolated a compound that kills bacteria that can cause incurable infections. The compound, called cloacaenodin, is a short, slip-knotted chain of amino acids known as a lasso peptide, encoded by gut-dwelling bacteria as a defense mechanism. The peptide works by attacking rival bacteria.

Their study, “Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter,” is published in the journal ACS Infectious Diseases and led by A. James Link, PhD, professor of chemical and biological engineering at Princeton.

“Using genome mining and heterologous expression, we report the discovery and production of a new antimicrobial lasso peptide from species related to the Enterobacter cloacae complex,” wrote the researchers. “Using NMR and mass spectrometric analysis, we show that this lasso peptide, named cloacaenodin, employs a threaded lasso fold which imparts proteolytic resistance that its unthreaded counterpart lacks.”

The peptide hooks into a target cell’s RNA-producing enzymes and shuts down basic cell functions.

“Not only does [this peptide] kill off-the-shelf, historical Enterobacter strains, it also kills Enterobacter strains that actually have come from patients in the hospital and that are drug-resistant,” explained Link.

Link’s research group has discovered several peptides in this same class. He said cloacaenodin is unique because it can kill clinically relevant drug-resistant strains, making it a promising subject for antibiotic development.

“If it’s made by one Enterobacter species, it’s likely going to kill other species of Enterobacter. So it’s this sort of guilt-by-association approach,” Link said. This gives researchers a way to prioritize peptide-mining hits, since peptides that are encoded in strains related to pathogens are more likely to have interesting bioactivity, he said.

The researchers plan to start testing the compound in animal infection models to confirm that it can clear the infection and that it is safe for animal cells.

Their findings suggest if the compound is harnessed by science, it could be redirected to fight infections that are not treatable by today’s medicines.