THE STRUCTURE OF AN ASYMMETRIC DIMER RELEVANT TO THE MODE OF ACTION OF THE GLYCOPEPTIDE ANTIBIOTICS

Background: Glycopeptide antibiotics of the vancomycin group are of cr ucial clinical importance in the treatment of methicillin resistant St aphylococcus aureus (MRSA) - the often lethal 'super-bug' - characteri zed by its resistance to a wide range of antibiotics in common use. Th e antibiotics exert their physiological action by blocking cell wall s ynthesis through recognition of nascent cell wall mucopeptides termina ting in the sequence -D-Ala-D-Ala. Evidence suggests that the antibiot ics are able to enhance their biological activity by the formation of homodimers, and this is supported by the observation that dimerization and peptide binding in vitro are cooperative phenomena. The basis of this enhancement is not understood at the molecular level. Results: Th e first detailed structure of a dimeric glycopeptide antibiotic, that of eremomycin, is presented based upon solution NMR data. The overall structure of the dimer complex is asymmetric. The source of this asymm etry - a parallel alignment and mutual interaction of the disaccharide s - appears to promote dimerization through specific sugar-sugar recog nition. Conclusions: A molecular basis for the observed cooperativity of cell wall peptide binding by eremomycin is evident from these studi es of the dimer. The carboxylate anion of the cell wall component, whi ch is crucial to binding, forms an amide-mediated ion-pair interaction to the alkylammonium ion of the ring 6 sugar in the other half of the dimer making the structure and positioning of this sugar important in mediating cooperativity.