Researchers design synthetic peptide to kill antibiotic-resistant bacteria

Researchers at the Indian Institute of Science (IISc) have designed a short peptide capable of poisoning a key enzyme in disease-causing bacteria, including some of most deadly and antibiotic-resistant species.

Made from a short stretch of about 24 amino acids, the peptide mimics the action of a natural toxin which inhibits a class of enzymes called topoisomerases. These enzymes play a crucial role in unspooling and re-coiling bacterial DNA during replication and protein synthesis. They are an attractive target for antibiotics because the ones in bacteria are very different from those in humans.

Topoisomerases form a covalent adduct – an intermediate complex – with the bacterial DNA, to coil or uncoil it. The peptide developed by the IISc team binds to this adduct and "traps" it in place, kicking off a cascade of events that lead to cell death, explains Raghavan Varadarajan, Professor at the Molecular Biophysics Unit (MBU), and one of the corresponding authors of the study published in EMBO Reports. This is similar to how a natural toxin called CcdB, produced by certain other bacteria and plasmids, works.

The full length CcdB protein is large. It is not feasible to use it as a drug in its entirety," says first author Jayantika Bhowmick, former Ph.D. student at MBU and currently a postdoctoral researcher at the University of Cambridge. Instead, the team snipped out a small stretch from the tail end of this protein and added a few more amino acids that would allow the new peptide to enter bacterial cells.

Image source: Jayantika Bhowmick.