Combinatorial Library Approach for the Identification of Synthetic Receptors Targeting Vancomycin-Resistant Bacteria
Combinatorial Library Approach for the Identification of Synthetic Receptors Targeting Vancomycin-Resistant Bacteria
复制标题
用于鉴定针对万古霉素耐药细菌的合成受体的组合文库方法
DOI：
10.1021/ja990240i
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发表时间：
1999
影响因子：
15
通讯作者：
J. Ellman
中科院分区：
文献类型：
--
作者：
R. Xu;G. Greiveldinger;Linda E. Marenus;A. Cooper;J. Ellman
糖肽类抗生素万古霉素对革兰氏阳性菌有活性，是治疗许多耐甲氧西林菌株（包括金黄色葡萄球菌菌株和多重耐药肺炎链球菌菌株）引起的严重感染的首选药物。1.万古霉素全球临床耐药性的出现具有明确、严重的临床后果。1万古霉素主要通过抑制细胞壁肽聚糖交联发挥其杀菌作用，该交联通过在关键附着位点与粘肽前体单元的末端L-Lys-D-Ala-D-Ala 2结合。抗性是通过以L-Lys-D-Ala-D-Lac结尾的改变的细胞壁前体的生物合成来实现的。3用D-乳酸盐取代末端D-丙氨酸引入排斥静电相互作用代替氢键，导致结合亲和力降低约1000倍（图1）。4合成的与L-Lys-D-Ala-D-Lac高亲和力结合的受体的鉴定为克服万古霉素耐药提供了一个强有力的策略。然而，设计在水溶液中结合分子的合成受体是一项艰巨的任务，以前只取得了很小的成功。6在此，我们报道了在水溶液中与L-Lys-D-Ala-D-Lac结合比万古霉素紧密5倍以上的合成受体。这项工作不仅产生了针对该靶标的最有效的合成受体，而且还代表了受体文库合成和筛选用于鉴定在水溶液中结合小分子的合成受体的首次成功应用。在我们的受体设计策略中，我们选择保留万古霉素的右侧羧酸结合口袋，以保留D-Ala-D-Lac和D-Ala-D-Ala复合物常见的氢键网络和疏水相互作用的重要元素。7分子的左手侧被可变的三肽单元取代（图2）。因为
The glycopeptide antibiotic vancomycin is active against Grampositive bacteria and is the drug of choice for the treatment of serious infections due to many methicillin-resistant strains including Staphylococcus aureus strains and multiply resistant strains of Streptococcus pneumoniae. 1 The emergence of global clinical resistance to vancomycin has clear, serious clinical consequences. 1 Vancomycin exerts its main bactericidal effect through inhibition of cell wall peptidoglycan cross-linking by binding to the terminal L-Lys-D-Ala-D-Ala2 of the mucopeptide precursor units at the crucial site of attachment. Resistance is effected by the biosynthesis of an altered cell wall precursor ending in L-Lys-D-Ala-D-Lac. 3 Replacement of the terminal D-alanine with D-lactate introduces a repulsive electrostatic interaction in place of a hydrogen bond resulting in a∼ 1000-fold reduction in binding affinity (Figure 1). 4The identification of synthetic receptors that bind with high affinity to L-Lys-D-Ala-D-Lac could provide a powerful strategy for overcoming vancomycin resistance. 5 However, the design of synthetic receptors that bind molecules in aqueous solution is a daunting task, and only minimal success has previously been achieved. 6 Herein, we report synthetic receptors that bind L-Lys-D-Ala-D-Lac greater than 5-fold more tightly than vancomycin in aqueous solution. This work not only has resulted in the most potent synthetic receptor toward this target but also represents the first successful application of receptor library synthesis and screening for the identification of synthetic receptors that bind small molecules in aqueous solution. In our receptor design strategy we chose to preserve the righthand carboxylate binding pocket of vancomycin in order to retain a significant element of the hydrogen-bonding network and hydrophobic interactions that are common to the D-Ala-D-Lac and D-Ala-D-Ala complexes. 7 The left-hand side of the molecule is replaced with a variable tripeptide unit (Figure 2). Because the