AsianScientist (Jul. 26, 2019) – A team of scientists in Japan has identified multiple promising new drug candidates to treat antibiotic-resistant infections, including the superbug MRSA (methicillin-resistant Staphylococcus aureus). They published their work in the journal Nature Communications.
Due to the widespread and irresponsible use of antibiotics, both for farming and for the treatment of diseases not caused by bacteria, several drug-resistant bacterial strains have emerged in the past decade. Even the last-resort antibiotic daptomycin is now less effective in treating MRSA infections, auguring a possible return to times when minor injuries or illnesses were fatal.
Recognizing the threat of drug-resistant bacteria, scientists are scrambling to discover or synthesize new antibiotics. In this study led by Assistant Professor Hiroaki Itoh at the University of Tokyo, Japan, researchers have devised a technique to enhance the infection-fighting potential of natural chemicals and test them quickly.
The team first identified promising new natural antibiotic from a soil sample collected in the subtropical island of Okinawa in southwestern Japan. The antibiotic, called lysocin E, has a unique mechanism of killing bacteria compared to the currently available classes of antibiotics—it binds to a component of the bacterial membrane to trigger cell death.
Lysocin E has a complex chemical structure that resembles a tambourine: a large ring with 12 short side chains. The protein building blocks, called amino acids, which form those chains, each contribute to the overall function of the entire molecule. Swapping the naturally occurring amino acids for different ones could enhance the function of the antibiotic.
“We tried to find the improvements that natural selection did not make yet,” said Itoh.
Researchers focused on four side chains and tested how seven different amino acids might enhance lysocin E’s antibacterial activity. All possible combinations of the four side chains and seven amino acids meant that researchers needed to build 2,401 different synthetic versions of modified lysocin E.
The researchers were able to build the entire range of 2,401 modified lysocin E compounds simultaneously, one amino acid at a time on top of tiny beads. The beads were divided into seven portions each time researchers arrived at a part of the molecule where they wanted to vary the amino acid in a side chain. Then all the beads were recombined until the next time an amino acid variation needed to be inserted.
“Very few researchers have done this before because many naturally-occurring molecules have relatively large and complex structures. This makes them difficult to build synthetically,” explained Itoh.
The researchers termed their technique a one-bead-one-compound library strategy, or split-and-mix synthesis.
Once all 2,401 modified lysocin E variants were built, the researchers tested if the bacteria-killing function of each variant was retained. The molecules were then removed from the beads for chemical structure analysis.
Only 22 of the modified lysocin E compounds were selected for the final round of tests to measure how effective they were at killing six common bacteria. Of those, 11 showed antimicrobial activity better or equal to the original lysocin E.
The researchers will study the three most potent modified lysocin E variants—defined by the very small amount of drug needed to effectively kill bacteria—in non-human animal models. They will also investigate how the synthetic compounds kill bacteria at such low doses.
“Potentially, our method could be used to find other drug candidates, based on promising small protein natural products, for the treatment of viral infections and cancer,” said Itoh.
The article can be found at: Itoh et al. (2019) Development of a High-throughput Strategy for Discovery of Potent Analogues of Antibiotic Lysocin E.
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Source: University of Tokyo; Photo: Shutterstock.
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