The role of hydrophobic substituents in the biological activity of glycopeptide antibiotics
The role of hydrophobic substituents in the biological activity of glycopeptide antibiotics
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DOI：
10.1021/ja0027665
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发表时间：
2000-12-20
影响因子：
15
通讯作者：
Kahne, D
中科院分区：
文献类型：
--
作者：
Kerns, R;Dong, SD;Kahne, D
万古霉素和替柯planin（图1、1a和2a）是临床使用的两种糖肽类抗生素。1这些药物通过与肽聚糖前体的末端D-Ala-D-Ala二肽结合，阻止细菌细胞壁的成熟（方案1）。2细菌通过产生以D-Ala-D-Lac结尾的细胞壁前体，对万古霉素和替柯planin产生耐药性，D-Ala-D-Lac是一种仅与药物的肽结合袋微弱相互作用的沉淀肽配体。这种抗生素耐药性的出现对人类健康构成严重威胁。4然而，通过在万古霉素的万古胺氮上附着疏水取代基来克服耐药性是可能的（图1,3a）。虽然teicoplanin （2a）含有天然存在的疏水取代基，但它对产生D-Ala-D-Lac肽末端的抗vana菌株的活性不如这些万古霉素衍生物（3a）（表1）。我们一直在探索疏水取代基在万古霉素衍生物生物活性中的作用，通过改变其位置。在本文中，我们报道了一类在葡萄糖C6位置上含有疏水取代基的新万古霉素衍生物的合成和评价（图1、4a和5a）。和替柯蛋白一样，这类化合物在糖上有疏水取代基，直接连接到苷元上。下面我们展示了4a和5a的行为更像teicoplanin而不是vancosamine取代的衍生物3a，这表明疏水取代基的位置影响作用机制。
Vancomycin and teicoplanin (Figure 1, 1a and 2a) are the two glycopeptide antibiotics that are used clinically. 1 These drugs function against gram positive bacteria by binding to the terminal D-Ala-D-Ala dipeptide of peptidoglycan precursors, preventing maturation of the bacterial cell wall (Scheme 1). 2 Bacteria become resistant to vancomycin and teicoplanin by producing cell wall precursors terminating in D-Ala-D-Lac, a depsipeptide ligand that interacts only weakly with the peptide binding pockets of the drugs. 3 The emergence of such antibiotic resistance poses a serious threat to human health. 4 However, it is possible to overcome resistance by attaching a hydrophobic substituent to the vancosamine nitrogen of vancomycin (Figure 1, 3a). 5 Although teicoplanin (2a) contains a naturally occurring hydrophobic substituent, it is not as active as these vancomycin derivatives (3a) against VanA-resistant strains producing D-Ala-D-Lac peptide termini (Table 1).We have been probing the role of the hydrophobic substituent in the biological activity of vancomycin derivatives by varying its position. In this paper, we report the synthesis and evaluation of a new class of vancomycin derivatives containing hydrophobic substituents on the glucose C6 position (Figure 1, 4a and 5a). Like teicoplanin, this class of compounds has the hydrophobic substituent on the sugar directly attached to the aglycone. Below we show that 4a and 5a behave more like teicoplanin than like the vancosamine-substituted derivative 3a, indicating that the position of the hydrophobic substituent influences the mechanism of action.