Isolation and structure of platencin: A FabH and FabF dual inhibitor with potent broad-spectrum antibiotic activity
Isolation and structure of platencin: A FabH and FabF dual inhibitor with potent broad-spectrum antibiotic activity
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DOI：
10.1002/anie.200701058
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Singh, Sheo B.
中科院分区：
文献类型：
--
作者：
Jayasuriya, Hiranthi;Herath, Kithsiri B.;Singh, Sheo B.
抗生素治疗细菌感染的发现是过去60年来最重要的医学成就之一。[1]然而，细菌对当前抗生素耐药性的出现是医学界面临的重大挑战。耐药性的出现是不可避免的，因此继续发现具有新作用模式的新型化学型抗生素对于克服耐药性生物体至关重要。[2]已经出现了几种药物发现策略，包括通过化学操作对现有抗生素进行渐进式改进，以及基于基因组方法寻找新的药物靶点。另一种策略是研究已知抗生素抑制的生化途径或过程，并在途径中寻找尚未开发的靶标。采用这种方法的一个主要好处是，这些途径是药物干预的有效靶点。脂肪酸的合成就是这样一种途径。我们选择研究的目标是脂肪酸生物合成缩合酶FabH和FabF，它们是保守的，对细菌的生存力至关重要。[3-6]FabF靶标已经成为研究的主题超过20年，并且已经报道了两类抑制剂：[7-12]浅蓝菌素[13]和硫乳霉素[14-16]及其类似物。浅蓝菌素是FabF的共价修饰剂和选择性抑制剂，而硫乳霉素是FabH和FabF的双重抑制剂。然而，两者都表现出较差的抗菌活性（金黄色葡萄球菌MIC（最小抑菌浓度）64 μg/mL）。[17]这些酶的有效抑制剂有望开发出对现有药物无交叉耐药性的抗生素。我们采用了一种差异敏感性的方法，其中每个目标的差异表达，通过使用木糖诱导型启动子控制下的反义方法。[18]在该方法中，表达fabF/fabH反义RNA的菌株相对于对照菌株表现出对FabH-和/或FabF-特异性抑制剂的超敏性。[18]这使我们能够开发一种基于靶点的全细胞高通量筛选试验，用于发现FabH和FabF抑制剂。[19最近通过采用这种微分灵敏度全细胞双板琼脂扩散试验[19]筛选天然产物提取物，使我们发现了作为一种抗真菌药物的铂霉素（1）。
The discovery of antibiotics for the treatment of bacterial infections has been one of the most important medical achievements of the past 60 years.[1] However, the emergence of bacterial resistance to current antibiotics is a major challenge faced by the medical community. The emergence of resistance is inevitable, and hence the continued discovery of novel chemotype antibiotics with novel modes of action is critical to overcome drug-resistant organisms.[2] Several drugdiscovery strategies have emerged, including incremental improvements to existing antibiotics by chemical manipulation and the search for novel drug targets on the basis of genomic approaches. An alternative strategy is to study the biochemical pathways or processes inhibited by known antibiotics and look for as yet unexploited targets within a pathway. A major benefit of employing such an approach is that these pathways are validated targets for drug intervention. The fatty acid synthesis is one such pathway. The targets we chose to study were the fatty acid biosynthesis condensing enzymes FabH and FabF, which are conserved and essential for bacterial viability.[3–6] The FabF target has been the subject of studies for over 20 years, and two classes of inhibitors have been reported:[7–12] cerulenin [13] and thiolactomycin [14–16] and its analogues. Cerulenin is a covalent modifier and a selective inhibitor of FabF, whereas thiolactomycin is a dual inhibitor of FabH and FabF. However, both exhibit poor antibacterial activity (Staphylococcus aureus MIC (minimum inhibitory concentration) 64 μg mLÀ1).[17] Potent inhibitors of these enzymes are expected to allow the development of antibiotics with no cross-resistance to existing drugs. We employed a differential-sensitivity method in which each target was differentially expressed by using antisense methodology under control of a xylose-inducible promoter.[18]In this method, the strain expressing fabF/fabH antisense RNA exhibits hypersensitivity to FabH-and/or FabF-specific inhibitors relative to a control strain.[18] This allowed us to develop a target-based whole-cell high-throughput-screening assay for the discovery of FabH and FabF inhibitors.[19, 20] Recent screening of natural product extracts by employing this differential-sensitivity whole-cell two-plate agardiffusion assay [19] led us to discover platensimycin (1) as a