Dimerization and membrane anchors in extracellular targeting of vancomycin group antibiotics

Antibiotics of the vancomycin group are shown to enhance their affinities for the bacterial cell wall by the devices of either dimerization (vancomycin and other glycopeptides which dimerize even more strongly) or use of a membrane anchor (teicoplanin); a chelate mechanism is suggested in both cases, as supported by antagonism experiments with the cell wall analog di-N-acetyl-L-Lys–D-Ala–D-Ala. These results may have implications for other binding processes which occur near membrane surfaces. Recent reviews of structure-activity relationships for antibi-otics of the vancomycin group (10) have not considered dimer-ization of the antibiotics, which we now believe plays an im-portant role in the mode of action (5, 8, 9, 16). Here, we present results consistent with a mechanism by which dimeric (e.g., vancomycin [Fig. 1A]) and lipoylated (e.g., teicoplanin [Fig. 1C]) glycopeptides enhance the binding affinities to their cellular targets by preferential location of the antibiotic near the site of cell wall biosynthesis. The antibacterial activities of vancomycin antibiotics resul