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The cleavage and isomerization of 3‘,5‘-uridyluridine catalyzed by morpholine buffers and by imidazole buffers has been reinvestigated. The key evidence for a previously proposed partitioning mechanismin which the buffer acid BH+ converts the substrate to a phosphorane monoanion intermediate which then partitions either to the 2‘,5‘ isomer of the substrate or (with buffer base catalysis) to the cleavage productis confirmed. The negative catalytic effect of the buffer base on the isomerization reaction is not due to a medium effect. Indeed the medium effect on this reaction is in the opposite direction, strengthening the catalytic evidence. However, this branching mechanism with sequential bifunctional catalysis of the cleavage reaction is accompanied by an additional cleavage path using the buffer base only. This additional path, for which several alternative mechanisms are possible, is required by the results of improved studies on the imidazole catalysis. These show that the previously reported decrease...

Because teicoplanin and vancomycin are the last line of defense for many bacterial infections, the emergence of resistance to glycopeptide antibiotics in enterococci and streptococci has aroused concern. Despite their similarity in terms of structure and mechanism of action, vancomycin induces the expression of genes that leads to bacterial resistance, and teicoplanin does not. We have used a combination of chemical and enzymatic methods to produce sets of vancomycin and teicoplanin analogues that allow us to consider whether the aglycon, the carbohydrate, or other parts of these molecules stimulate VanB resistance. We show that the teicoplanin and vancomycin aglycons are the structural elements that lead to induction of resistance. We think that lipid-containing analogues of vancomycin, like teicoplanin itself, circumvent resistance because the lipid chain changes the periplasmic distribution of the glycopeptide and, therefore, changes the biosynthetic step that it blocks.