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Anacor Identifies a Novel Mechanism for Its Lead Anti-Fungal Drug,,AN2690; Findings Published in Science

e European Molecular Biology Laboratory (EMBL) in Grenoble, France, led by Stephen Cusack, Ph.D., then determined how the drug worked at the molecular level.

By examining fungal strains resistant to the drug, scientists determined that the drug blocks protein synthesis by inhibiting a protein called leucyl-tRNA synthetase, or LeuRS. LeuRS plays a key role in translating the genetic code in both fungus and bacteria, and blocking its action keeps those organisms from growing, effectively stopping the infection. Researchers found that replacing the boron atom in AN2690 with a carbon atom inactivated the drug, underscoring the importance of the boron chemistry.

While the anti-fungal effect of the LeuRS protein inhibition by boron-containing compounds has been established by the clinical results seen for AN2690, other proteins from the same family, known as aminoacyl-tRNA synthetases, are well-validated targets for antibiotic drug development.

"Now that we know how AN2690 works, the same approach could be adapted to target other aminoacyl-tRNA synthetases with editing sites, which are also excellent targets for anti-microbial drugs," said Cusack, whose group performed the X-ray crystallography which revealed how AN2690 binds to LeuRS.

Anacor is now leveraging that knowledge to create new boron-containing drugs designed to target systemic bacterial infections.

"Drug-resistant bacteria are a large and growing problem in the hospital and in the community, which makes the discovery of novel antibiotics a public health necessity," said David Perry, Anacor's chief executive officer. "We believe that our approach may hold great promise in the development of these needed therapies."

Boron is a naturally occurring element found in the soil and in water supplies. It is an essential micronutrient for plants, and the chemical is commonly present in its elemental form in the human bloodstream. Despite the ubiquity of the element, little work
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