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 crucial clinical importance in the treatment of methicillin resistant Staphylococcus aureus (MRSA)--the often lethal 'super-bug'--characterized by its resistance to a wide range of antibiotics in common use. The antibiotics exert their physiological action by blocking cell wall synthesis through recognition of nascent cell wall mucopeptides terminating in the sequence -D-Ala-D-Ala. Evidence suggests that the antibiotics 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

The 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 asymmetry--a parallel alignment and mutual interaction of the disaccharides--appears to promote dimerization through specific sugar-sugar recognition.

CONCLUSIONS

A molecular basis for the observed cooperativity of cell wall peptide binding by eremomycin is evident from these studies of the dimer. The carboxylate anion of the cell wall component, which 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.