Structural requirements for VanA activity of vancomycin analogues

We have prepared several sets of glycopeptide analogues in order to probe the molecular basis for the activity of derivatives that overcome vanA resistance. The results described in this paper provide compelling evidence that good vanA activity is due to a mechanism of action that does not involve peptide binding. Hypothesizing that this mechanism of action involves an interaction of the disaccharide portion of vancomycin analogues with bacterial transglycosylases, we have prepared a compound in which the vancomycin aglycone is coupled to a known transglycosylase inhibitor that is structurally unrelated to the disaccharides that have been previously investigated. The activity of this compound is excellent. This work provides a clear prescription for the design of better glycopeptide analogues.