Synthetic peptide to kill deadly bacteria resisting antibiotics

Bengaluru: Indian Institute of Science (IISc) researchers have designed a short peptide — short chains of amino acids — which they say can poison a key enzyme in disease-causing bacteria, including some of the 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,” IISc said in a statement.Topoisomerases play a crucial role in unspooling and re-coiling bacterial DNA during bacterial replication and protein synthesis. They are an attractive target for antibiotics because the ones in bacteria are very different from those in humans, it added. Among the most widely used antibiotics are fluoroquinolones such as ciprofloxacin, which target these topoisomerases. However, overuse of these antibiotics around the world has led to alarming rise of antibiotic-resistant bacteria, prompting scientists to pursue alternative strategies and molecules. The peptide the team has developed intervenes in topoisomerases, enabling bacterial unspooling and recoiling and kicking off a cascade of events that lead to cell death, explained Raghavan Varadarajan, professor, molecular biophysics unit (MBU), and one of the corresponding authors of the study published in EMBO Reports. The peptide is similar to how a natural toxin called CcdB, produced by certain other bacteria and plasmids, works. First author of the paper, Jayantika Bhowmick, said: “The full length of CcdB protein is large. It’s not feasible to use it as a drug in its entirety.” Instead, Bhowmick, a former PhD student at MBU and currently a postdoctoral researcher at the University of Cambridge, said 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. The team tested the new peptide’s effect on the growth of several disease-causing bacterial species, including E. coli, Salmonella Typhimurium, Staphylococcus aureus and a multidrug resistant strain of Acinetobacter baumanii — both in cell culture as well as animal models — in collaboration with the lab of Dipshikha Chakravortty, professor, department of microbiology and cell biology.“They also compared the effect of their peptide against clinical doses of ciprofloxacin. Depending on the species, the peptide was found to either block or “poison” a specific type of topoisomerase — an enzyme called DNA gyrase — in many of them. It’s [also] capable of disrupting most of the strains’ membranes,” explained Manish Nag, PhD student at MBU.