Use of a Bacteriophage Lysin Antibody to Identify a Novel Target for Antimicrobial Development
Congratulations to our friend and colleague Dr. Allan Goldberg and his team from Rockefeller University for this breakthrough research.
Target selection is critical for the development of new antimicrobial agents. To date, most approaches for target selection have focused on the importance of bacterial survival. However, in addition to survival, according an article published in CPLoS ONE (10 April 2013), it is believed that molecular targets should be identified by determining which cellular pathways have a low probability for developing resistance.
The article identifies an essential cell wall biosynthetic enzyme that has been identified in Bacillus anthracis, as well as an inhibitor to which the organism did not spontaneously evolve measurable resistance. This work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have evolved to recognize critical receptors within the bacterial cell wall. Focusing on the B. anthracis-specific PlyG lysin, the authors first identified its unique cell wall receptor and cognate biosynthetic pathway. Within this pathway, one biosynthetic enzyme, 2-epimerase, was required for both PlyG receptor expression and bacterial growth.
Through the collaboration with Astex, initiated by co-author Allan Goldberg, an inhibitor of 2-epimerase named Epimerox was developed. Raymond Schuch, a former postdoctoral researcher in Fischetti’s lab at Rockefeller, tested the inhibitor in mice infected with Bacillus anthracis. He found that not only did Epimerox protect the animals from anthrax, but the bacteria did not develop resistance to the inhibitor. The researchers also found that Epimerox was able to kill methicillin-resistant Staphylococcus aureus (or MRSA) with no evidence of resistance even after extensive testing.