Institut für Biochemie, Universität Greifswald, Greifswald, Germany.
FEBS Lett. 2011 Apr 6;585(7):1061-6. doi: 10.1016/j.febslet.2011.03.012. Epub 2011 Mar 12.
The flavin-dependent monooxygenase TetX confers resistance to all clinically relevant tetracyclines, including the recently approved, broad-spectrum antibiotic tigecycline (Tygacil®) which is a critical last-ditch defense against multidrug-resistant pathogens. TetX represents the first resistance mechanism against tigecycline, which circumvents both the tet-gene encoded resistances, relying on active efflux of tetracyclines, and ribosomal protection proteins. The alternative enzyme-based mechanism of TetX depends on regioselective hydroxylation of tetracycline antibiotics to 11a-hydroxy-tetracyclines. Here, we report the X-ray crystallographic structure determinations at 2.1Å resolution of native TetX from Bacteroides thetaiotaomicron and its complexes with tetracyclines. Our crystal structures explain the extremely versatile substrate diversity of the enzyme and provide a first step towards the rational design of novel tetracycline derivatives to counter TetX-based resistance prior to emerging clinical observations.
黄素依赖单加氧酶 TetX 赋予了对抗所有临床相关四环素类药物的抗性，包括最近批准的广谱抗生素替加环素（Tygacil®），后者是对抗多药耐药病原体的关键最后防线。TetX 是针对替加环素的第一种耐药机制，它绕过了 tet 基因编码的耐药性，依赖于四环素类药物的主动外排和核糖体保护蛋白。TetX 的替代酶基机制依赖于四环素类抗生素的区域选择性羟化，生成 11a-羟基四环素类。在这里，我们报告了来自拟杆菌属的天然 TetX 及其与四环素类药物复合物的 X 射线晶体结构测定，分辨率为 2.1Å。我们的晶体结构解释了该酶极其多样的底物多样性，并为在出现临床观察之前针对基于 TetX 的耐药性进行新型四环素衍生物的合理设计提供了第一步。
