Park Jooyoung, Gasparrini Andrew J, Reck Margaret R, Symister Chanez T, Elliott Jennifer L, Vogel Joseph P, Wencewicz Timothy A, Dantas Gautam, Tolia Niraj H
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
Nat Chem Biol. 2017 Jul;13(7):730-736. doi: 10.1038/nchembio.2376. Epub 2017 May 8.
Although tetracyclines are an important class of antibiotics for use in agriculture and the clinic, their efficacy is threatened by increasing resistance. Resistance to tetracyclines can occur through efflux, ribosomal protection, or enzymatic inactivation. Surprisingly, tetracycline enzymatic inactivation has remained largely unexplored, despite providing the distinct advantage of antibiotic clearance. The tetracycline destructases are a recently discovered family of tetracycline-inactivating flavoenzymes from pathogens and soil metagenomes that have a high potential for broad dissemination. Here, we show that tetracycline destructases accommodate tetracycline-class antibiotics in diverse and novel orientations for catalysis, and antibiotic binding drives unprecedented structural dynamics facilitating tetracycline inactivation. We identify a key inhibitor binding mode that locks the flavin adenine dinucleotide cofactor in an inactive state, functionally rescuing tetracycline activity. Our results reveal the potential of a new tetracycline and tetracycline destructase inhibitor combination therapy strategy to overcome resistance by enzymatic inactivation and restore the use of an important class of antibiotics.
尽管四环素是农业和临床中使用的一类重要抗生素，但其疗效正受到耐药性增加的威胁。对四环素的耐药性可通过外排、核糖体保护或酶失活产生。令人惊讶的是，尽管四环素酶失活具有抗生素清除的明显优势，但在很大程度上仍未得到充分研究。四环素破坏酶是最近从病原体和土壤宏基因组中发现的一类使四环素失活的黄素酶家族，具有广泛传播的高潜力。在这里，我们表明四环素破坏酶以多样且新颖的方向容纳四环素类抗生素进行催化，并且抗生素结合驱动了前所未有的结构动力学，促进四环素失活。我们确定了一种关键的抑制剂结合模式，该模式将黄素腺嘌呤二核苷酸辅因子锁定在无活性状态，从功能上挽救了四环素的活性。我们的结果揭示了一种新的四环素和四环素破坏酶抑制剂联合治疗策略的潜力，该策略可通过酶失活克服耐药性并恢复一类重要抗生素的使用。
