CHEMOENZYMATIC APPROACH TOWARD THE SYNTHESIS OF VANCOMYCIN AND ITS ANALOGUES

Abstract

Vancomycin, the first and founding member of the glycopeptide antibiotics, has been in clinical use since 1958 in the fight against bacterial infections. Due to its efficiency in treating multi drug-resistant bacteria, vancomycin has long been considered a drug of last resort. Antibiotic resistance has been recently observed to vancomycin like every other antibiotic that is currently on the market. Traditionally, synthetic tailoring has allowed us to repurpose ineffective antibiotics and reintroduce more effective derivatives back into the clinic, however, that is unfortunately not feasible with vancomycin because of its structural complexity. Herein, in collaboration with Seyedsayamdost group, we have developed a new platform for synthesizing vancomycin and useful vancomycin analogues, with the aim of repurposing this drug. In our approach, synthetic routes generate the monomeric amino acid units and the heptapeptide core of vancomycin, while the biosynthetic enzymes form three crosslinks and glycosidic bonds on the heptapeptide. The successful implementation of this chemoenzymatic approach, which combines the flexibility of chemical synthesis and the high selectivity of enzymatic synthesis, enables the preparation of vancomycin and the creation of new, perhaps improved, analogues in an efficient fashion.