Wang Jun, Kodali Srinivas, Lee Sang Ho, Galgoci Andrew, Painter Ronald, Dorso Karen, Racine Fred, Motyl Mary, Hernandez Lorraine, Tinney Elizabeth, Colletti Steven L, Herath Kithsiri, Cummings Richard, Salazar Oscar, González Ignacio, Basilio Angela, Vicente Francisca, Genilloud Olga, Pelaez Fernando, Jayasuriya Hiranthi, Young Katherine, Cully Doris F, Singh Sheo B
Merck Research Laboratories, Rahway, NJ 07065, USA.
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7612-6. doi: 10.1073/pnas.0700746104. Epub 2007 Apr 24.
Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Platencin shows potent in vivo efficacy without any observed toxicity. It targets two essential proteins, beta-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC50 values of 1.95 and 3.91 microg/ml, respectively, whereas platensimycin targets only FabF (IC50 = 0.13 microg/ml) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by using this antisense differential sensitivity whole-cell screening paradigm.
细菌耐药性的出现是所有抗生素类别面临的一个主要问题；因此，迫切需要鉴定新的抗生素类别。最近，我们报告了通过使用基于靶点的全细胞策略结合反义沉默技术并辅以无细胞生化验证来筛选天然产物提取物，从而发现了扁枝衣霉素。持续的筛选工作又导致发现了扁枝菌素，这是一种与扁枝衣霉素在化学和生物学上相关但不同的新型天然产物。扁枝菌素通过抑制脂肪酸生物合成表现出广谱的革兰氏阳性抗菌活性。它对所测试的关键抗生素耐药菌株，包括耐甲氧西林金黄色葡萄球菌、万古霉素中介金黄色葡萄球菌和耐万古霉素肠球菌，均未表现出交叉耐药性。扁枝菌素在体内显示出强大的疗效且未观察到任何毒性。它作用于两种必需蛋白，β-酮酰基-[酰基载体蛋白（ACP）]合酶II（FabF）和III（FabH），其IC50值分别为1.95和3.91微克/毫升，而在金黄色葡萄球菌中扁枝衣霉素仅作用于FabF（IC50 = 0.13微克/毫升），这强调了通过使用这种反义差异敏感性全细胞筛选模式可以发现更多具有新颖结构和新作用模式的抗生素这一事实。
