Phillips John W, Goetz Michael A, Smith Scott K, Zink Deborah L, Polishook Jon, Onishi Russell, Salowe Scott, Wiltsie Judyann, Allocco John, Sigmund Janet, Dorso Karen, Lee Suzy, Skwish Stephen, de la Cruz Mercedes, Martín Jesús, Vicente Francisca, Genilloud Olga, Lu Jun, Painter Ronald E, Young Katherine, Overbye Karen, Donald Robert G K, Singh Sheo B
Infectious Diseases, Merck Research Laboratories, Merck & Co, Rahway, NJ 07065, USA.
Chem Biol. 2011 Aug 26;18(8):955-65. doi: 10.1016/j.chembiol.2011.06.011.
Bacterial resistance to known therapeutics has led to an urgent need for new chemical classes of antibacterial agents. To address this we have applied a Staphylococcus aureus fitness test strategy to natural products screening. Here we report the discovery of kibdelomycin, a novel class of antibiotics produced by a new member of the genus Kibdelosporangium. Kibdelomycin exhibits broad-spectrum, gram-positive antibacterial activity and is a potent inhibitor of DNA synthesis. We demonstrate through chemical genetic fitness test profiling and biochemical enzyme assays that kibdelomycin is a structurally new class of bacterial type II topoisomerase inhibitor preferentially inhibiting the ATPase activity of DNA gyrase and topoisomerase IV. Kibdelomycin is thus the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades.
细菌对已知治疗药物产生耐药性，这导致迫切需要新型化学类别的抗菌剂。为解决这一问题，我们将金黄色葡萄球菌适应性测试策略应用于天然产物筛选。在此，我们报告发现了束丝放线菌素，这是由束丝孢囊菌属的一个新成员产生的一类新型抗生素。束丝放线菌素具有广谱革兰氏阳性抗菌活性，是DNA合成的有效抑制剂。我们通过化学遗传学适应性测试分析和生化酶测定证明，束丝放线菌素是一种结构新型的细菌II型拓扑异构酶抑制剂，优先抑制DNA旋转酶和拓扑异构酶IV的ATP酶活性。因此，束丝放线菌素是六十多年来从天然产物来源发现的首个具有强效抗菌活性的真正新型细菌II型拓扑异构酶抑制剂。
