The Biosynthesis of Liposidomycin-like A-90289 Antibiotics Featuring a New Type of Sulfotransferase
The Biosynthesis of Liposidomycin-like A-90289 Antibiotics Featuring a New Type of Sulfotransferase
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DOI：
10.1002/cbic.200900665
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发表时间：
2010-01-25
期刊：
影响因子：
3.2
通讯作者：
Van Lanen, Steven G.
中科院分区：
文献类型：
--
作者：
Funabashi, Masanori;Baba, Satoshi;Van Lanen, Steven G.
参与肽聚糖细胞壁生物合成的酶已被证明是抗菌药的靶标，这些药物已经给医学带来了革命性的变化。值得注意的是，参与肽聚糖生物合成的大多数酶还没有在临床上得到开发。[2]细菌易位I(也被注释为mray)，它通过将UDP-N-乙酰胞壁酸-五肽转移到十一烯基磷酸来启动肽聚糖细胞壁生物合成的脂质循环。[3]由于耐药病原体的出现和重新出现，[4]由于肽聚糖在细菌生存中的基本性质，以及在哺乳动物中缺乏细菌转位酶I的活性，Mray是设计和开发新抗生素的一个有吸引力的目标。最近几个实验室的研究表明，几种结构多样化的天然产品可以有效地抑制细菌转位酶I。[3]这包括几个核苷类抗生素家族，它们具有相对于临床使用的抗生素独特的化学支架。脂霉素属于一类被称为脂肪酰基核苷的核苷类抗生素家族，也包括从链霉菌中分离出来的卡普扎霉素。[5]脂胞菌素的结构于1988年首次报道，[6]其结构由四个部分组成，即5‘-C-甘草酸尿苷、2’-磺化氨基核糖、二氮丙酮和可变碳链长度的β-羟基脂肪酸部分，在β-位上有不寻常的3-甲基戊二酰基修饰。与脂霉素不同，卡普扎霉素含有额外的全甲基化鼠李糖，缺乏2‘-O-硫酸盐部分。[5]在筛选抑制细菌转位酶I的新化合物的过程中，我们从链霉菌中分离出了一系列相关的化合物。击沉了60405架名为A-90289的带有道具的-
Enzymes involved in peptidoglycan cell wall biosynthesis are proven targets for antibacterial drugs that have revolutionized medicine.[1] Remarkably, however, the majority of the enzymes involved in peptidoglycan biosynthesis have yet to be exploited in the clinic.[2] Bacterial translocaseI (also annotated as MraY), which initiates the lipid cycle of peptidoglycan cell wall biosynthesis by transfer of phospho-N-acetylmuramic acid-pentapeptide from UDP-N-acetylmuramic acid-pentapeptide to undecaprenyl phosphate, represents one such enzyme for which there are no marketed antibiotic drugs.[3] Given the emergence and re-emergence of drug-resistance pathogens,[4] the essential nature of peptidoglycan in the viability of bacteria, and the lack of a bacterial translocase I activity in mammals, MraY is an attractive target for the design and development of new antibiotics.Recent efforts in several laboratories have revealed that several structurally diverse natural products potently inhibit bacterial translocase I.[3] This includes several families of nucleoside antibiotics that have unique chemical scaffolds relative to clinically used antibiotics. The liposidomycins belong to one such family of nucleoside antibiotics called fatty acyl nucleosides that also includes the caprazamycins isolated from Streptomyces sp. MK730-62F2.[5] The liposidomycins, the structure of which was initially reported in 1988,[6] are characterized by four moieties, a 5’-C-glycyluridine, a 2’-sulfated aminoribose, a diazepanone, and a β-hydroxy fatty acid moiety of variable carbon chain length modified with an unusual 3-methylglutaryl group at the β-position. Caprazamycins, in contrast to liposidomycins, contain an additional permethylated rhamnose and lack the 2’-O-sulfate moiety.[5] During screening for new compounds that inhibit bacterial translocase I, we isolated a series of related compounds from Streptomyces sp. SANK 60405 termed A-90289s that had prop-