A NEW CLASS OF SYNTHETIC ANTIBACTERIALS ACTING ON LIPOPOLYSACCHARIDE BIOSYNTHESIS
A NEW CLASS OF SYNTHETIC ANTIBACTERIALS ACTING ON LIPOPOLYSACCHARIDE BIOSYNTHESIS
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DOI：
10.1038/327730a0
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发表时间：
1987-06-25
期刊：
影响因子：
64.8
通讯作者：
EKSTROM, B
中科院分区：
文献类型：
--
作者：
HAMMOND, SM;CLAESSON, A;EKSTROM, B
尽管需要仅作用于革兰氏阴性细菌的抗菌剂，但目前此类化合物很少。β-KDO(3-脱氧-β-D-甘露-2-辛基吡喃糖酸)的2-脱氧类似物是革兰氏阴性菌脂多糖生物合成的关键酶(CMPKDO合成酶)的有效抑制剂，但它不能穿透完整的细菌1。将L-L二肽偶联到β-KDO的8-氨基-2，8-二脱氧类似物上，使其被细胞膜上的某些多肽识别并主动积聚。二肽在细胞内被水解，并释放出抑制剂。随后抑制CMP-KDO合成酶导致大量类脂A前体积累和细菌死亡。这些化合物代表了一类新的合成抗菌剂，具有新的作用机制和作为化疗药物的相当大的潜力。
Although there is a need for antibacterial agents that act only on Gram-negative bacteria, there are at present few such compounds. The 2-deoxy analogue ofβ-KDO (3-deoxy-β-D-manno-2-octulopyranosonic acid) is a potent inhibitor of a key enzyme (CMP-KDO synthetase) in lipopolysaccharide biosynthesis of Gram-negative bacteria, but it fails to penetrate intact bacteria1. Coupling an L-L-dipeptide to the 8-amino-2,8-dideoxy analogue ofβ-KDO enabled it to be recognized and actively accumulated by certain peptide permeases of the cytoplasmic membrane. The dipeptide was hydrolysed in the cell and the inhibitor released. Subsequent inhibition of CMP-KDO synthetase led to the accumulation of large amounts of lipid A precursor and bacterial death. These compounds represent a new class of synthetic antimicrobials with a novel mechanism of action and considerable potential as chemotherapeutic agents.