Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design.
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.
Yuan
Yanqiu
Y
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Fuse
Shinichiro
S
Ostash
Bohdan
B
Sliz
Piotr
P
Kahne
Daniel
D
Walker
Suzanne
S
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry* / Q000494:pharmacology*; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000201:enzymology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009844:Oligosaccharides; D046928:Peptidoglycan Glycosyltransferase; C419802:moenomycin