Tigecycline Is Modified by the Flavin-Dependent Monooxygenase TetX

Citations Over TimeTop 19% of 2005 papers

Abstract

The clinical use of tetracycline antibiotics has decreased due to the emergence of efflux and ribosomal protection-based resistance mechanisms. Currently in phase III clinical trials, the glycylcycline derivative tigecycline (GAR-936) containing a 9-tert-butylglycylamido group is part of a new generation of tetracycline antibiotics developed during the 1990s. Tigecycline displays a broad spectrum of antibacterial activity and circumvents the efflux and ribosomal protection resistance mechanisms. The TetX protein is a flavin-dependent monooxygenase that modifies first and second generation tetracyclines and requires NADPH, Mg(2+), and O(2) for activity. We report that tigecycline is a substrate for TetX and that bacterial strains containing the tet(X) gene are resistant to tigecycline. The resistance is due to the modification of tigecycline by TetX to form 11a-hydroxytigecycline, which we have shown has a weakened ability to inhibit protein translation compared with tigecycline. We have explored the basis of this decreased ability to block translation and found that hydroxylation occurs in the region of the molecule important for coordinating magnesium. 11a-Hydroxytigecycline forms a weaker complex with magnesium than tigecycline; the crystal structure of tetracycline in complex with the ribosome has shown that magnesium coordination is critical for binding tetracycline. Although tet(X) has not been isolated from any clinically resistant strains, our report demonstrates the first enzymatic resistance mechanism to tigecycline and provides an alert for the surveillance of resistant strains that may contain tet(X).

Related Papers

• → Presence of Tetracycline Resistance Determinants and Susceptibility to Tigecycline and Minocycline(2005)115 cited
• → Efflux pumps may play a role in tigecycline resistance in Burkholderia species(2010)26 cited
• → Coexistence of blaNDM-1, blaOXA-51, blaOXA-23, and armA in conjunction with novel mutations detected in RND efflux pump regulators in tigecycline resistant clinical isolates of Acinetobacter baumannii(2022)12 cited
• → Screening of an Inhibitor of the Tetracycline Efflux Pump in a Tetracycline-Resistant Clinical-Isolate of Staphylococcus aureus 743.(1998)15 cited