Abstract:
:Peptidoglycan glycosyltransferases (PGTs), enzymes that catalyze the formation of the glycan chains of the bacterial cell wall, have tremendous potential as antibiotic targets. The moenomycins, a potent family of natural product antibiotics, are the only known active site inhibitors of the PGTs and serve as blueprints for the structure-based design of new antibacterials. A 2.8 A structure of a Staphylococcus aureus PGT with moenomycin A bound in the active site appeared recently, potentially providing insight into substrate binding; however, the protein-ligand contacts were not analyzed in detail and the implications of the structure for inhibitor design were not addressed. We report here the 2.3 A structure of a complex of neryl-moenomycin A bound to the PGT domain of Aquifex aeolicus PBP1A. The structure allows us to examine protein-ligand contacts in detail and implies that six conserved active site residues contact the centrally located F-ring phosphoglycerate portion of neryl-moenomycin A. A mutational analysis shows that all six residues play important roles in enzymatic activity. We suggest that small scaffolds that maintain these key contacts will serve as effective PGT inhibitors. To test this hypothesis, we have prepared, via heterologous expression of a subset of moenomycin biosynthetic genes, a novel moenomycin intermediate that maintains these six contacts but does not contain the putative minimal pharmacophore. This compound has comparable biological activity to the previously proposed minimal pharmacophore. The results reported here may facilitate the design of antibiotics targeted against peptidoglycan glycosyltransferases.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Yuan Y,Fuse S,Ostash B,Sliz P,Kahne D,Walker Sdoi
10.1021/cb800078asubject
Has Abstractpub_date
2008-07-18 00:00:00pages
429-36issue
7eissn
1554-8929issn
1554-8937journal_volume
3pub_type
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