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Scientists Discover Antibiotic Mechanism

Borrelidin (BN) simultaneously occupies the enzyme binding sites for L-threonine, tRNA, and ATP—plus an extra site.Image by the researchers, courtesy of Nature Communications.

The widespread use of antibiotics in modern society has led to a sharp rise in antibiotic-resistant bacteria. As a result, much research has focused on creating new compounds to fight these bacteria.

Borrelidin was isolated from the bacteria Streptomyces about 50 years ago. The compound has broad antibacterial, antifungal, antimalarial, anticancer, insecticidal, and herbicidal activities. It works by interfering with a type of essential enzyme called tRNA synthetase. These enzymes help cells make proteins through a process called translation. Their role is to attach amino acids (the building blocks of proteins) to molecules called transfer RNAs (tRNAs), which help add amino acids to a growing protein chain. Borrelidin blocks the action of threonyl-tRNA synthetase, thereby preventing the amino acid L-threonine from linking to its tRNA. The linking reaction occurs at the enzyme’s active site and also involves the energy molecule ATP.

A research team led by Dr. Min Guo of the Scripps Research Institute investigated how borrelidin interferes with threonyl-tRNA synthetase. They used a technique called X-ray crystallography to decipher the structure of the enzyme when borrelidin interacts with it. The study was funded in part by NIH’s National Institute of Environmental Health Sciences (NIEHS) and National Institute of General Medical Sciences (NIGMS). Results appeared in Nature Communications on March 31, 2015.

The researchers found that borrelidin simultaneously occupies the enzyme binding sites for L-threonine, tRNA, and ATP. Thus, the compound blocks all 3 molecules from the synthetase’s active site. As a result, L-threonine can’t be linked to its tRNA, and protein translation fails.

The researchers determined that borrelidin binding also causes a change to the structure of the enzyme that creates a fourth spot for borrelidin attachment. In a series of experiments, they confirmed the importance of this extra binding site for translation. Thus, borrelidin inhibits translation by binding to 4 sites that are necessary for threonyl-tRNA synthetase to function.

“This has never been seen in any other tRNA synthetase inhibitors, including the ones sold as medicines,” Guo says. “This finding establishes a new inhibitor class and highlights the striking design of this natural compound that inhibits tRNA synthetases in 2 of the 3 kingdoms of life.”

Researchers have been investigating the potential of tRNA synthetase inhibitors to fight bacteria, fungi, cancers, and autoimmune diseases. The insights from this research may help guide scientists in the rational design of improved, more selective drugs.

— by Brandon Levy and Harrison Wein, Ph.D.