Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase

作者：Gesa Volkers, Gottfried Julius Palm, M.S. Weiss, Gerard D. Wright, Winfried Hinrichs · 发表于：FEBS Letters · 年份：2011 · DOI：10.1016/j.febslet.2011.03.012 · 被引用次数：126 · 研究领域：Antibiotic Resistance in Bacteria、Pharmaceutical and Antibiotic Environmental Impacts、Bacterial Genetics and Biotechnology

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.