EMBL: blocked protein synthesis unravels fungi-killing compound

Research lead

Scientists at the European Molecular Biology Laboratory in Grenoble have elucidated the mode of action of an antifungal drug being developed by the US biotech company Anacor Pharmaceuticals and say the finding could lead to the development of a new class of anti-infective drugs.

The scientists have worked out that Anacor’s compound, AN2690, kills fungi by blocking their ability to make proteins.

AN2690 inhibits an enzyme, leucyl-tRNA synthetase, which is involved in translation, one of the last steps in the process of gene expression.

Stephen Cusack and colleagues generated crystals of the enzyme bound to tRNA in the presence of AN2690 and found that AN2690 sticks in the editing site of the enzyme, where it makes a very strong bond to the end of the tRNA, trapping it on the enzyme.

The mode of action depends on a boron atom on AN2690, which is needed to link the compound to the tRNA. This is the first time such a mechanism has been described, and the scientist suggest that boron containing compounds could represent a new class of anti-infective drugs.

“Now that we know how AN2690 works, the same approach could be adapted to target other aminoacyl-tRNA synthetases with editing sites, and also other pathogenic microbes,” said Cusack. “We are now working towards finding related antibacterial compounds that could help counter the problem of antibiotic resistance.”