Platensimycin is a selective FabF inhibitor with potent antibiotic properties
Platensimycin is a selective FabF inhibitor with potent antibiotic properties
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DOI：
10.1038/nature04784
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发表时间：
2006-05-18
期刊：
影响因子：
64.8
通讯作者：
Singh, SB
中科院分区：
文献类型：
--
作者：
Wang, J;Soisson, SM;Singh, SB
由于对现有抗生素出现耐药性，细菌感染仍然是对人类生命的严重威胁。尽管科学界热衷于发现与新靶点相互作用的新抗生素，但自20世纪60年代初以来，这些努力取得的成功有限(1，2)。在这里，我们报告了Plensimycin的发现，这是一种以前未知的由钝顶链霉菌产生的抗生素。Platensimycin通过选择性地抑制细胞脂质生物合成而显示出强大的广谱革兰氏阳性抗菌活性。我们证明，这种抗菌作用是通过选择性靶向脂肪酸合成途径中的β-酮酰基-(酰基载体蛋白(ACP))合成酶I/II(FabF/B)来实现的。直接结合分析表明，铂新霉素与目标蛋白的酰基酶中间体发生了特异性的相互作用，X射线结晶学研究表明，在酰化反应中，抑制剂必须发生特定的构象变化才能结合。用铂新霉素治疗小鼠可根除金黄色葡萄球菌感染。由于其独特的作用模式，铂新霉素对其他关键的耐药菌株没有交叉耐药性，包括耐甲氧西林的金黄色葡萄球菌、万古霉素中间的金黄色葡萄球菌和耐万古霉素的肠球菌。Platensimycin是已报道的对FabF/B缩合酶最有效的抑制剂，也是唯一具有广谱活性、体内疗效和未观察到毒性的这些靶标的抑制剂。
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s(1,2). Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein(ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/ B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.