Biologists Decode an Ancient Cancer-Fighting Antibiotic

Borrelidin is as ancient as it is effective. A potent defense against bacterial and fungal infections, tumors, and Malaria, the borrelidin molecule first found use (in a slightly different form) 2,000 years ago in China as a treatment for Malaria-induced fever. Now, for the first time, scientists have uncovered the particular mechanism that makes it so powerful.

The new research comes courtesy of biologists at the Scripps Research Institute—led by professor Min Guo—and is described the current issue of Nature Communications.

Something that's both this powerful and broad enough to target basically the entire range of human disease would seem to be almost too good to be true, but the things that make us sick aren't as different as they always seem. At the very least, they all require new proteins.

It turns out that the key is in blocking an enzyme known as threonyl-tRNA synthetase (ThrRS) which is necessary for the production of proteins, the building blocks required for any sort of life to grow and thrive (or exist). It had been shown previously, for example, that borrelidin blocks the formation of new blood vessels in malignant tumors, as well as fostering the process of cell death known as apoptosis in leukemia, encouraging cancerous self-destruction.

The effectiveness of borrelidin in inhibiting thrRS, a member of a larger category of enzymes known as AARS, is in mimicry. To do its protein-fostering work, an AARS enzyme needs a substrate, which is sort of like a foundation for a chemical process. This foundation requires several other molecules, which chemically bind to the AARS in different places​

The exact molecules that bind to these enzymes vary between fungi, bacteria, tumors, and parasitic protozoans, but borrelidin doesn't discriminate, binding to three key sites required for the enzymes to be effective. In this way it "crowds out" the stuff AARS needs to construct a suitable substrate.

That borrelidin (and its sibling compounds) work is nothing new. "For example, the natural product mupirocin inhibits [synthetase] activity and is approved as a topical treatment for bacterial skin infections," Guo and his group write. "Febrifugine is the active component of the Chinese herb Chang Shan (Dichroa febrifuga Lour), which has been used for treating malaria-induced fever for about 2,000 years." Meanwhile, another related compound, febrifugine, has been shown to be effective against cancer and fibrosis. Another relative, AN2690, has found use in fighting the fungal infection onychomycosis. This is already popular stuff.

But the potential of borrelidin is just getting started. Now that biologists know how it works, the next task is in making it more effective. There's no such thing as a legit cure-all, but naturally occurring, broadly-effective compounds like it are the next best thing.

"This has never been seen in any other tRNA synthetase inhibitors, including the ones sold as medicines," Guo offers in a statement. "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."