A new mechanism to attack hard-to-treat fungal infections has been revealed by scientists from the biotech company Anacor Pharmaceuticals Inc., California, and the European Molecular Biology Laboratory (EMBL) outstation in Grenoble, France. In the current issue of Science they describe how a new compound kills fungal pathogens by blocking an enzyme crucial for their protein synthesis.
The human body is home to many different kinds of fungi. While the majority normally do not harm us, some fungi can cause unpleasant infections of skin, nails or lungs.
We have discovered a new compound that has the potential to treat common chronic nail infections caused by fungi, says Dickon Alley, researcher at Anacor Pharmaceuticals. The compound, called AN2690, kills fungi by blocking their ability to make proteins.
AN2690 interferes with an enzyme called leucyl-tRNA synthetase, which is involved in translation, one of the last steps in the process of turning a genes DNA code into a protein. The process begins when the cell makes an RNA version of the genes code, called messenger RNA. Ribosomes, the cells protein synthesis machinery, then translate the messenger RNA into protein by stitching together the amino acids in the order specified by the message. This requires the help of molecules called tRNAs, which link the code of the messenger RNA to the correct amino acid.
Leucyl-tRNA synthetase is one of a group of enzymes called aminoacyl-tRNA synthetases that attach the correct amino acid to each tRNA. Some of these enzymes have two main functional parts, or active sites: a site that links the amino acid to the tRNA, and a separate editing site that proofreads this process and removes wrongly added amino acids.
To find out how exactly AN2690 blocks leucyl-tRNA synthetase Stephen Cusack, Head of EMBL Grenoble, and his team generated crystals of the enzyme bound to tRNA in the presence of AN2690. Examining them with the high-intensity X-ray source at th
Contact: Anna-Lynn Wegener
European Molecular Biology Laboratory