Researchers develop new technique to enhance the infection control potential of natural chemicals

Japanese researchers have identified several promising new drug candidates to treat antibiotic-resistant infections, including superbug MRSA (methicillin-resistant). Staphylococcus aureus). The team has developed a new technique to enhance the anti-infective potential of natural chemicals and test them quickly.

In laboratory tests, three of the synthetic molecules built by the researchers are four times more effective at killing bacteria than their natural predecessor, which is already an order of magnitude more powerful than the drug currently used against MRSA, vancomycin.

Our technique is fast because we can build thousands of new molecules in a single synthesis. "

Hiroaki Itoh, Assistant Master, Department of Pharmaceutical Sciences of the University of Tokyo

The researchers first identified the promising new natural antibiotic from a soil sample taken from the subtropical island of Okinawa, in southwestern Japan. The antibiotic, called lysocine E, has a unique mechanism for killing bacteria compared to the clbades of antibiotics currently available. Even MRSA would be defenseless against it.

Lysocine E has a complex chemical structure that resembles a tambourine: a large ring with 12 short side chains.

The protein components, called amino acids, which form these chains, each contribute to the overall function of the molecule. The exchange of amino acids of natural origin against different amino acids could improve the function of the antibiotic.

"We are trying to find the improvements that natural selection has not yet made," Itoh said.

The researchers focused on four side chains and tested how seven different amino acids could increase the antibacterial activity of lysocine E. All possible combinations of the four side chains and the seven amino acids forced the researchers to create 2 401 different synthetic versions of modified lysocine E.

The researchers simultaneously constructed the 2 401 modified lysocine E, an amino acid on both small beads. The beads were divided into seven portions each time the researchers reached part of the molecule where they wanted to vary the amino acid in a side chain. Then all the beads were recombined until the researchers reached the location of the next variation of amino acids.

"Very few researchers have done so because many natural molecules have relatively large and complex structures, which makes them difficult to construct in a synthetic way," Itoh explained.

This technique is known as a library strategy to a pearl, a compound or synthesis by mixing.

Once the 2,401 modified lysocines E were constructed, the researchers checked whether they retained the unique method of destroying the bacteria of the natural version. The researchers then removed the molecules from the beads and identified their chemical structures.

Only 22 modified lysocine E were selected for the last series of tests to measure their effectiveness in destroying six common bacteria in small test tubes. Of these, 11 modified lysocine E showed antimicrobial activity greater than or equal to that of lysocine E.

Researchers will study the three most potent modified lysocine E – defined by the very small amount of drug effective at killing bacteria – to test their effectiveness in treating infections in nonhuman animal models and to understand the detailed mechanism of the destruction of bacteria at such low doses.

"Our method could potentially be used to find other promising natural product-based drug candidates based on small proteins, including anti-cancer or anti-viral drugs," Itoh said.

The researchers are confident that their synthetic enhancement method of natural products can accelerate drug discovery at an early stage and help maximize the potential of existing complex molecules in the natural state.

In addition to bacteria, pathogens, including HIV (viruses) and malaria (parasites), become drug-resistant, increasing the potential for drug resistance to global health. For more information on antibiotic resistance, see the World Health Organization fact sheet: https://www.who.int//www.who.int /writing/cards /detail/antibiotic resistance