Enzymatic Glycosylation of Vancomycin Aglycon: Completion of a Total Synthesis of Vancomycin and N- and C‑Terminus Substituent Effects of the Aglycon Substrate

ABSTRACT: Studies on the further development of the sequential glycosylations of the vancomycin aglycon catalyzed by the glycosyltransferases GtfE and GtfD and the observation of unusual, perhaps unexpected, aglycon substrate substituent effects on the rate and efficiency of the initial glycosylation reaction are reported. The glycopeptide antibiotics are the most important class ofdrugs used for the treatment of resistant bacterial infections that include those caused by methicillin-resistant Staphylococcus aureus (MRSA).1,2 After more than 50 years of clinical use, the emergence of vancomycin-resistant Gram-positive pathogens, including not only vancomycin-resistant Enterococci (VRE)3 but also the more recent vancomycin-resistant S. aureus (VRSA),4 presents an imminent challenge to public health at a time few new antibiotics are being developed. This has led to renewed interest in the search for additional effective treatments for such resistant organisms that possess the long-term durability of the two clinically used glycopeptide antibiotics, vancomycin5 (Figure 1) and teicoplanin.1,2,