Synthetic and biological studies on vancomycin and moenomycin analogues.

摘要

Vancomycin is a glycopeptide antibiotic that is widely used to treat Gram-positive bacterial infections. The emergence of resistance to vancomycin has caused considerable concern in recent years. Previous experiments in our laboratory have suggested that some glycolipid derivatives of vancomycin are bifunctional, consisting of two components that interact with two types of targets on the bacterial cell wall. The first mode of action involves binding to the peptide termini of peptidoglycan precursors and blocking the enzymes involved in peptidoglycan synthesis. The second mechanism involves direct inhibition of transglycosylases, the peptidoglycan synthesizing enzymes. Based on these results, a series of hybrid antibiotics that are comprised of the vancomycin aglycon attached to molecules with transglycosylase inhibitory activity were synthesized and evaluated. Moenomycin is a known inhibitor of transglycosylases. A series of moenomycin disaccharide derivatives were synthesized and coupled to the vancomycin aglycon to make hybrid compounds. These compounds have good activities against both sensitive and resistant bacteria. A transglycosylase assay suggested that these glycopeptides inhibit penicillin-binding protein 1b (PBP1b), the major transglycosylase in E. coli, via a direct interaction with the enzyme. This work suggests opportunities for the design of a class of new antibiotics comprised of hosts that bind to cell surface peptides attached to specific inhibitors for peptidoglycan-processing enzymes.; Transglycosylase is an excellent antibacterial target because it is essential to bacterial cell survival. Moenomycin has outstanding antibiotic activity due to its inhibition of the transglycosylases. Moenomycin has not been developed for human use because of its poor physical properties. A better understanding of its mechanism of action would be helpful in the design of new antibiotics. Moreover, moenomycin is a challenging molecule that has never been chemically synthesized. As a part of the synthetic studies on moenomycin and its derivatives, the lipid portion of moenomycin, moenocinol, was synthesized, and the synthesis of the allylic ether linkage of the glycerate-moenocinol portion was investigated. The utility of the sulfoxide glycosylation using acceptors with C3 and C4 unprotected hydroxyl groups to make beta-1, 4-glycosidic linkages between two N-acylated sugars (C and E rings of moenomycin) were also explored.