Expanding antibiotic targets

Many antibiotics inhibit enzymes involved in the synthesis of bacterial cell walls, but the problem of antibiotic resistance is driving researchers to develop drugs that attack different target enzymes. The enzyme transglycosylase (TG) is an excellent target but still lacks an antibiotic. Chi-Huey Wong and Che Ma of the Genomics Research Center of Academia Sinica, Taiwan, and colleagues therefore analyzed TG in the antibiotic-resistant bacterium, Staphylococcus aureus¹. This enzyme catalyzes the incorporation of peptidoglycan subunits into the bacterial cell wall. The subunits are carried to the enzyme by a molecule known as lipid II.

After determining the crystal structure of the TG enzyme bound to a lipid II analog, the team used mutagenesis studies to identify which parts of the enzyme’s catalytic site are most conserved and therefore most significant. This allowed them to propose modified details of the enzyme mechanism, and to identify two amino acids within the enzyme's structure that perform crucial roles that could be targeted for inhibition by drugs.

“TG is considered an excellent target, but antibiotics have not been developed to interact with this enzyme, partly because of a lack of detailed understanding of its structure and mechanism. Our work should help the search for drug candidate molecules,” Wong notes.