Structure-based gene targeting discovery of sphaerimicin, a bacterial translocase I inhibitor.
Structure-based gene targeting discovery of sphaerimicin, a bacterial translocase I inhibitor.
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DOI：
10.1002/anie.201305546
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发表时间：
2013-10-25
影响因子：
16.6
通讯作者：
Van Lanen, Steven G.
中科院分区：
文献类型：
--
作者：
Funabashi, Masanori;Baba, Satoshi;Takatsu, Toshio;Kizuka, Masaaki;Ohata, Yasuo;Tanaka, Masahiro;Nonaka, Koichi;Spork, Anatol P.;Ducho, Christian;Chen, Wei-Chen Leyla;Van Lanen, Steven G.
关键词：
据估计，传染病和寄生虫病是全球第二大致死原因，由于耐药病原体的稳步上升，这一问题正变得越来越严重。[1]耐药性的增加也与过去几十年市场上抗生素数量的减少不谋而合。[2]自然，开发新的抗生素对全球人类健康至关重要，特别是那些具有新的作用模式和/或独特的化学结构的抗生素。在这里，我们提出了球菌素A的发现，这是一种硫化的聚酮-核苷杂化产物，可以被认为符合这两个描述。肽聚糖细胞壁在细菌的生存中起着至关重要的作用，因此，抑制其生物合成已被证明是治疗细菌感染的革命性措施。[3]几乎所有的细菌都最少依赖12种保守的酶来安装细胞壁，有趣的是，这些酶中的大多数还没有成功地被商业抗生素靶向(图S1)。其中大多数是细菌磷酸-N-乙酰胞壁氨基-五肽转位酶(Translocase I，简记为mray)，它通过催化磷酸-N-乙酰胞壁酸-五肽从UDP-N-乙酰胞壁酸-五肽转移到十一烯基磷酸，从而启动肽聚糖生物合成的脂质循环，释放UMP产生十一烯-二磷酸-N-乙酰胞壁酸-五肽，或Lipid I。在过去的十年中，在将mray基因产物与转位酶活性连接后不久，[4]出现了几种有效的、利用基于活性的筛选已经发现了天然产物抑制剂。[5]大多数抑制剂在结构上被归类为尿苷类核苷，其中典型的核呋喃核糖通过CC键在C-5‘位被修饰以生成所谓的高碳糖核苷。[5]这些高碳糖核苷根据核心支架被进一步划分为亚基，包括那些含有非蛋白生成氨基酸5’-C-甘草酸(GlyU)的核苷，如1-5所示的那些或具有尿苷-5‘-甲酰胺(Caru)核的那些，如6-8(图1)所示。
Infectious and parasitic disease is estimated to be the second leading cause of death worldwide and is becoming increasingly problematic due to the steady rise in drug resistant pathogens.[1] The increase in resistance has also coincided with decreasing numbers of antibiotics brought to the market for the past few decades.[2] Naturally, it is paramount to global human health that new antibiotics are developed, particularly those with novel modes of action and/or unique chemical structures. Herein we present the discovery of sphaerimicin A, a sulfated hybrid polyketide-nucleoside that can be considered to fit both of these descriptors.Peptidoglycan cell wall plays an essential role in the viability of bacteria, and as a result the inhibition of its biosynthesis has proven to be revolutionary for treating bacterial infections.[3] Nearly all bacteria rely minimally on twelve conserved enzymes to install the cell wall, and intriguingly, the majority of these enzymes have yet to be successfully targeted by commercial antibiotics (Figure S1). One of this majority is bacterial phospho-N-acetylmuramyl-pentapeptide translocase (translocase I, annotated as MraY), which initiates the lipid cycle of peptidoglycan biosynthesis by catalyzing the transfer of phospho-N-acetylmuramic acid-pentapeptide from UDP-N-acetylmuramic acid-pentapeptide to undecaprenyl phosphate, releasing UMP to generate undecaprenyl-disphospho-N-acetylmuramic acid-pentapeptide, or Lipid I. Within the past decade and shortly after connecting the mraY gene product with the translocase activity,[4] several potent, natural product inhibitors have been discovered using activity-based screens.[5] Most of the inhibitors are structurally categorized as uridine-based nucleosides wherein the canonical ribofuranose is modified at the C-5′ position via a CC bond to generate a so-called highcarbon sugar nucleoside.[5] These high-carbon sugar nucleosides are further divided into subgroups based on the core scaffold, which includes those containing the nonproteinogenic amino acid 5′-C-glycyluridine (GlyU) exemplified by 1–5 or those with a uridine-5′-carboxamide (CarU) core exemplified by 6–8 (Figure 1).[6]
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影响因子：
--
作者：
Chi X;Baba S;Tibrewal N;Funabashi M;Nonaka K;Van Lanen SG
通讯作者：
Van Lanen SG
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
3.3
作者：
Funabashi, Masanori;Nonaka, Koichi;Van Lanen, Steven G.
通讯作者：
Van Lanen, Steven G.
影响因子：
2.1
作者：
Hirano, Shinpei;Ichikawa, Satoshi;Matsuda, Akira
通讯作者：
Matsuda, Akira
影响因子：
4.8
作者：
Kaysser, Leonard;Lutsch, Liane;Gust, Bertolt
通讯作者：
Gust, Bertolt