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Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase
Author(s) -
Volkers Gesa,
Palm Gottfried J.,
Weiss Manfred S.,
Wright Gerard D.,
Hinrichs Winfried
Publication year - 2011
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2011.03.012
Subject(s) - tetracycline , mechanism (biology) , chemistry , monooxygenase , resistance (ecology) , computational biology , biochemistry , microbiology and biotechnology , biophysics , biology , enzyme , ecology , physics , antibiotics , cytochrome p450 , quantum mechanics
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 2.1 Å 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.