Designing new biological molecules to fight bacteria and cancer
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 lasso-shaped, 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 his graduate student Jessica (Si Jia) Pan have created a dozen variants with more antibiotic potency. The researchers use 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 bacteria 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 a bacteria evolves resistance, we can try to evolve peptides that overcome that resistance.”
While Link’s approach to designing drugs is experimental, Christodoulos Floudas, the Stephen C. Macaleer Professor of Chemical and Biological Engineering, has spent more than a decade developing computational methods for the same purpose.
Floudas and his graduate students have found a way to calculate whether a peptide, based on its structure and amino-acid sequence, will bind to a specific protein. They have designed seven new peptides that bind to a human enzyme linked to cancer progression. Experiments by a Boston company have shown that the peptides inhibit the enzyme’s function. “There’s no currently available inhibitor for this enzyme,” Floudas said.