Groves P, Searle M S, Mackay J P, Williams D H
Cambridge Centre for Molecular Recognition, University Chemical Laboratories, UK.
Structure. 1994 Aug 15;2(8):747-54. doi: 10.1016/s0969-2126(94)00075-1.
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.
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.
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.
万古霉素类糖肽抗生素在治疗耐甲氧西林金黄色葡萄球菌（MRSA）——这种通常致命的“超级细菌”方面具有至关重要的临床意义，其特点是对多种常用抗生素具有耐药性。这些抗生素通过识别以-D-丙氨酰-D-丙氨酸序列结尾的新生细胞壁粘肽来阻断细胞壁合成，从而发挥其生理作用。有证据表明，这些抗生素能够通过形成同二聚体来增强其生物活性，体外二聚化和肽结合是协同现象这一观察结果也支持了这一点。这种增强作用在分子水平上的基础尚不清楚。
基于溶液核磁共振数据，给出了二聚体糖肽抗生素埃瑞霉素的首个详细结构。二聚体复合物的整体结构是不对称的。这种不对称性的来源——二糖的平行排列和相互作用——似乎通过特定的糖-糖识别促进了二聚化。
从对二聚体的这些研究中可以明显看出埃瑞霉素结合细胞壁肽时观察到的协同作用的分子基础。对结合至关重要的细胞壁成分的羧酸根阴离子与二聚体另一半中6位环糖上的烷基铵离子形成酰胺介导的离子对相互作用，这使得该糖的结构和定位在介导协同作用中很重要。
