The persistent threat of antimicrobial drug-resistance has scientists continually searching for compounds with a unique mechanism of action to circumvent resistance and hopefully prevent the initiation of new resistance pathways.
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) believe they have uncovered a unique antimicrobial mechanism for a small molecule, originally derived from Actinomyces bacteria, called borrelidin that could serve as template for new drug design.
The findings from this study were published recently in Nature Communications through an article entitled “Structural Basis for Full-Spectrum Inhibition of Translational Functions on a tRNA Synthetase.”
“Our study may help the rational design of compounds similar to borrelidin with a range of useful applications, particularly in cancer,” said Min Guo, Ph.D., associate professor of cancer biology at TSRI Florida and senior author on the study.
Compounds that are similar to borrelidin have been used previously to treat bacterial skin infections and malaria induced fever. Dr. Guo and his team wanted to understand how borrelidin and similar compounds exerted their effects. The researchers knew from previous studies that borrelidin inhibited the enzyme threonyl-tRNA synthetase (ThrRS), ultimately preventing protein synthesis.
“It is probably the most potent tRNA synthetase inhibitor on Earth,” stated Pengfei Fang, Ph.D., research associate in the Guo lab and co-first author of the current study. “It is also the earliest known tRNA synthetase inhibitor, discovered in 1966—just a few years after people learned the existence of tRNA synthetase and genetic code.”
Additionally, Xue Yu, Ph.D., research associate in the Guo lab and also co-first author on the study, emphasized, “While little is known about how borrelidin works, the fairly widespread use of these types of inhibitors highlights their tremendous potential in a number of medical applications.”
The TSRI team performed detailed structural and functional analyses on the binding properties of borrelidin to both human and E. coli ThrRS. What they discovered was that borrelidin occupies four distinct sites on both human and bacterial ThrRS—all three normal binding sites as well as an additional site that is formed when the compound binds. Essentially, borrelidin eliminates any possible chance of protein synthesis by crowding out all molecules that would typically bind.
Dr. Guo and his team were quite surprised at their functional analysis findings, since each of the binding sites is essential for ThrRS activity, borrelidin uses an apparent overkill strategy that accounts for its potency.
“This has never been seen in any other tRNA synthetase inhibitors, including the ones sold as medicines,” said Dr. Guo. “This finding establishes a new inhibitor class and highlights the striking design of this natural compound that inhibits tRNA synthetases in two of the three kingdoms of life.”