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 the most deadly and antibiotic-resistant species.

The peptide is made from a short stretch of about 24 amino acids, mimicking the action of a natural toxin that inhibits a class of enzymes called topoisomerases.

Moreover, these enzymes play a crucial role in unspooling and re-coiling bacterial DNA during replication and protein synthesis and are an attractive target for antibiotics because the ones in bacteria are very different from those in humans, noted the researchers.

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Among the most widely used antibiotics are fluoroquinolones such as ciprofloxacin, which target topoisomerases. Topoisomerases form a covalent adduct—an intermediate complex—with the bacterial DNA to coil or uncoil it.

However, it is observed that the overuse of these antibiotics around the world has led to the alarming rise of antibiotic-resistant bacteria, prompting scientists to pursue alternative strategies and molecules. 

IISc team’s peptide

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, explained Raghavan Varadarajan, Professor at the Molecular Biophysics Unit (MBU). This is also similar to how a natural toxin, CcdB, produced by certain other bacteria and plasmids, works. 

“The full-length CcdB protein is large, and it is not feasible to use it as a drug in its entirety. Rather, 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,” Jayantika Bhowmick, a postdoctoral researcher at the University of Cambridge, said.

Later, the peptide’s effect was tested 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 and in animal models.

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Furthermore, 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, said Manish Nag, Ph.D. student at MBU. “It is [also] capable of disrupting most of the strains’ membranes,” he added.

Animal models

In animal models, the peptide was found to drastically reduce infection. For instance, in animals infected with antibiotic-resistant Acinetabacter baumannii, the peptide treatment caused an 18-fold reduction in bacterial load in the liver, compared to only a 3-fold reduction by ciprofloxacin. The peptide was also found to be relatively safe and did not cause toxic reactions in the animals. 

“In most cases, we saw that the decline in the bacterial count in major organs following peptide treatment was higher than in the ciprofloxacin-treated group,” added Bhowmick.

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Since the peptide binds to a different site on the bacterial enzyme than ciprofloxacin, the researchers believe that it provides leads for the identification of drugs that can be used as a combination therapy with existing antibiotics. According to Varadarajan, the study also reinforces the importance of targeting topoisomerases as a valid approach to finding new antibiotics.  

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