| Vancomycin is an important antibacterial drug and the last line of defense against methicillin-resistant Staphylococcus aureus (MRSA). Bacterial resistance to vancomycin poses a serious public health threat. We have shown that carbohydrate derivatives of vancomycin can overcome resistance by mechanisms other than peptide binding and the carbohydrate moiety is important for the activity. To probe the role of the carbohydrates, three different approaches have been explored and the syntheses of three different types of molecules achieved.; The first vancomycin derivative with a non-native sugar attached by chemical glycosylation, desmethyl vancomycin, has been synthesized using the sulfoxide glycosylation method. The chlorobiphenyl-substituted derivative of this compound has excellent activity against MRSA.; To explore the possibility of making carbohydrate derivatives of vancomycin enzymatically using glycosyl transferases, the key substrate UDP-4- epi-vancosamine has been synthesized. It is the first synthesis achieved for any NDP-3-amino-2,3,6-trideoxy sugar.; To further explore carbohydrate diversity using chemistry that is easier, more flexible and more compatible with combinatorial library design, the linked vancomycin derivatives, in which the carbohydrate is connected to the aglycon via a linker, have been designed and synthesized. Subtle changes on vancosamine and the positioning of the hydrophobic substituent have been found to have dramatic effects on their activities. These results further suggest that there are specific interactions between the derivatized carbohydrates and their targets. The design and synthesis of the linked vancomycin derivatives provide a rapid entry to exploring vancomycin carbohydrate diversity, potentially leading to better drugs. |
