Lasso peptides round up bacteria

Lasso peptides

Assistant Professor James Link and graduate student Jessica (Si Jia) Pan are developing peptide drugs that could treat antibiotic-resistant infections.

Princeton researchers are applying Darwinian evolution principles to naturally occurring antibacterial molecules to create novel antibiotics for the food and drug industries.

Bacteria secrete antimicrobial peptides — short chains of amino acids — for defense against other species. James Link, an assistant professor of chemical and biological engineering, is pioneering research on a class of such peptides that are lassoshaped, which makes them resistant to the body’s defense mechanisms and hence good drug candidates. “We’re understanding how these amazing structures are made by bacteria,” Link said. “Thermodynamically they shouldn’t exist.”

Starting with one particular lasso peptide, Link and graduate student Jessica (Si Jia) Pan created a dozen variants with more antibiotic potency. The researchers used a method called directed evolution in which they create random mutations, test for desirable properties and repeat. They screened 20,000 variations of the peptide for the most promising molecules and found the most promising to be as potent as the antibacterial peptides used in the food industry to protect perishables.

The researchers are now trying to beat harmful, adaptive bacteria such as Escherichia coli at their own game. “We’re trying to use directed evolution to find a peptide that can kill E. coli that are resistant to it,” Link said. “In the same way that bacteria evolve resistance, we can try to evolve peptides that overcome that resistance.”

The work, which was published in the April 2011 issue of the Journal of the American Chemical Society, was funded in part by the National Science Foundation and Princeton’s Project X, which is designed to allow faculty members in the School of Engineering and Applied Science to pursue unconventional but promising research.