BORRELIDIN’S BLOCKING STRATEGY NATURAL PRODUCTS: Researchers discover that the potent antibiotic inhibits its target by multitasking
F
IFTY YEARS AGO, researchers plucked a highly
potent antibiotic out of a bacterial broth and named it borrelidin. Although scientists soon discovered that it blocked the activity of an enzyme involved in protein synthesis, no one could figure out exactly how it did so. Now, researchers led by Min Guo at Scripps Research Institute Florida report they have used X-ray crystallography to determine how borrelidin jams its protein target, threonyl-tRNA synthetase (Nat. Commun. 2015, DOI: 10.1038/ncomms7402). The structural insights could enable drug developers to massage the molecule, which also has potent antifungal, antimalarial, and anticancer properties, into a viable therapeutic. Borrelidin is one of several molecules that target transfer RNA synthetases, the protein machines that attach amino acids to tRNA, so that the ribosome can then add the amino acids to a growing protein chain. Other tRNA synthetase-blocking compounds are therapeutics, such as the topical ointment mupirocin (or bactroban), which can kill MRSA, the notorious methicillin-resistant Staphylococcus aureus. “For decades, borrelidin remained one of the most potent molecules in its class, yet people didn’t know how it worked,” comments Roger G. Linington, a natural products chemist at the University of California, Santa Cruz. Guo’s team discovered that borrelidin shuts down its target by being an impressive multitasker: The
molecule simultaneously blocks three substrate binding sites and creates its own fourth site by jamming its macrolide ring into the protein’s hydrophobic core. “The fact that it binds these four sites is incredible,” comments Michael Ibba, an Ohio State University microbiologist who studies tRNA O synthetases. “Nobody would have designed this OH molecule using a rational design strategy,” O N H Linington says. Only extensive evolutionO ary experimentation could lead to such a blocking mechanism, he adds. “Now we OH need to find out whether this is a common HO mode of action or just something freaky Borrelidin and weird about borrelidin,” Ibba says. Borrelidin is currently too unselective to be a drug. The molecule targets tRNA synthetases in humans, which could make for undesirable toxic side effects. It is also metabolized too quickly by the body, so its pharmacokinetic properties are poor, Guo adds. Guo hopes that the atomic-level structure of borrelidin in its target’s binding pocket will help researchers design more inhibitors of the tRNA synthetase and deBorrelidin (shown) velop borrelidin analogs that get around its selectivity is one of the most and pharmacokinetic problems. Tweaking borrelidin potent inhibitors of may be challenging synthetically, Linington notes, tRNA synthetases. because the molecule contains an unusual but important nitrile motif and conjugated olefins, all of which medicinal chemists may find hard to modify. One way to help borrelidin avoid human synthetases, Guo adds, could be to encapsulate the molecule chemically and target those bundles to pathogenic or cancerous cells.—SARAH EVERTS
CHEMICAL PLANTS Union Carbide to buy back troubled West Virginia facility The Institute Industrial Park in Institute, W.Va.—well-known among local residents for once producing lethal methyl isocyanate (MIC)—is returning to the firm that first set it up: Union Carbide, now a Dow Chemical subsidiary. Bayer CropScience is divesting the 460-acre site to Dow for an undisclosed amount. Dow is one of Bayer’s tenants at the park. Other firms at the Kanawha Valley chemical complex include FMC and the former Union Carbide industrial gas business Praxair. Union Carbide bought the site from the
U.S. government in 1947 to make products that eventually included MIC, an insecticide intermediate. After an MIC leak killed thousands of people in 1984 at a Union Carbide joint venture in Bhopal, India, West Virginia residents grew worried that a similar accident might occur there. Rhône-Poulenc bought the Institute facility from Carbide in 1986. Bayer acquired it in 2002. In 2008 a Bayer vessel at the site exploded, killing two workers. Shrapnel from the explosion came dangerously close to a storage tank containing 13,000 lb of MIC. Bayer started winding down the site’s
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MIC-based carbamate chemistry in 2011: It closed plants that made aldicarb and carbaryl insecticides, and it decided not to restart a shuttered MIC plant. Today, Bayer makes only thiodicarb, used in its Larvin insecticide, at the Institute plant. After transfer of the property and infrastructure to Dow, Bayer will remain as a tenant. “Without additional production capacity, Bayer CropScience does not have the critical mass needed to make continued ownership of the site economically viable,” says Jim Covington, Bayer’s head of the Institute Industrial Park.—ALEX TULLO
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