Health & Medicine, India (Commonwealth Union) – Researchers from the Indian Institute of Science (IISc) have successfully engineered a concise peptide capable of sabotaging a crucial enzyme found in disease-causing bacteria, including some of the most perilous and antibiotic-resistant strains.
Formed from merely 24 amino acids, the peptide imitates the mechanism of action employed by a natural toxin, which effectively inhibits a class of enzymes known as topoisomerases. These enzymes play a pivotal role in the unwinding and rewinding of bacterial DNA during replication and protein synthesis. Since the topoisomerases in bacteria differ significantly from those in humans, they serve as an attractive target for antibiotic development.
Among the commonly used antibiotics are fluoroquinolones, like ciprofloxacin, which specifically target these topoisomerases. However, the widespread misuse and overuse of such antibiotics globally have led to the alarming emergence of antibiotic-resistant bacteria. In response, scientists have been exploring alternative strategies and molecules to combat these pathogens.
Antibiotic resistance had pushed the need new treatments with many researchers from across the engaging in a race to develop new treatments from previously unexplored avenues to remedy the issue.
The newly developed peptide by the IISc team binds to a covalent adduct – an intermediate complex – formed between the bacterial DNA and the topoisomerases during the process of coiling or uncoiling. By binding to this adduct, the peptide effectively “traps” it in place, initiating a series of events that culminate in the death of the bacterial cell. Raghavan Varadarajan, a Professor at the Molecular Biophysics Unit (MBU) and one of the corresponding authors of the study published in EMBO Reports, explains that this process closely resembles the mode of action of a natural toxin called CcdB, which is produced by certain other bacteria and plasmids.
According to Jayantika Bhowmick, the first author of the study and a former PhD student at MBU who is currently a postdoctoral researcher at the University of Cambridge, the full-length CcdB protein is too large to be used as a drug. Therefore, the research team decided to extract a small segment from the end of the protein and incorporated a few additional amino acids to enable the newly designed peptide to penetrate bacterial cells. The development of this peptide was undertaken by the laboratory of Professor Jayanta Chatterjee in MBU.
Subsequently, the team conducted tests to evaluate the impact of the newly designed peptide on the growth of various disease-causing bacterial species. These species included E. coli, Salmonella Typhimurium, Staphylococcus aureus, and a multidrug-resistant strain of Acinetobacter baumannii. The evaluation was conducted both in cell culture and animal models in collaboration with the lab of Professor Dipshikha Chakravortty from the Department of Microbiology and Cell Biology (MCB). The researchers also compared the effects of their peptide with clinical doses of ciprofloxacin, an antibiotic commonly used to target bacteria.
Depending on the bacterial species, the peptide exhibited different actions. It was observed to either block or “poison” a specific type of enzyme called DNA gyrase in many of the bacteria. Manish Nag, another author of the study and a PhD student at MBU, explains that the peptide was also capable of disrupting the membranes of most of the tested bacterial strains.
In animal models, the peptide was noted to largely lower infection. “In most of the cases, we saw that the decline in the bacterial count in major organs following peptide treatment was higher than in the ciprofloxacin-treated group. That was pretty encouraging to us,” explained Bhowmick. The researchers gave an example, in animals infected with antibiotic-resistant Acinetabacter baumannii, where the peptide treatment made way for an 18-fold decrease of the bacterial load in the liver, when contrasted to just a 3-fold decrease by ciprofloxacin. It was further noted in the peptide to be relatively safe and brought about no toxic reactions in the animals.
