Tigecycline is a glycylcycline antibiotic with broad-spectrum activity including against tetracycline-resistant organisms. Which resistance mechanism(s) does tigecycline overcome that confers its advantage?

• A Overcomes both efflux pump-mediated and ribosomal protection-based tetracycline resistance, but is susceptible to novel metalloenzyme TetX ✓
• B Overcomes only ribosomal methylation resistance, still affected by efflux pumps
• C Not affected by any tetracycline resistance mechanism due to unique bulky side chain
• D Overcomes efflux resistance only; ribosomal protection remains effective against tigecycline

Explanation

Classical tetracycline resistance involves two main mechanisms: (1) efflux pumps (Tet(A), Tet(B), etc.) expelling tetracycline; (2) ribosomal protection proteins (Tet(M), Tet(O)) shielding the ribosome. Tigecycline's bulky 9-t-butylglycylamido substituent sterically hinders both the efflux pump binding sites and the ribosomal protection proteins, overcoming these mechanisms. However, tigecycline is susceptible to the flavoenzyme TetX (and its variants TetX3, TetX4) — a plasmid-borne monooxygenase that enzymatically hydroxylates and inactivates tigecycline (and all tetracyclines), representing an emerging resistance mechanism. Additionally, Pseudomonas and Proteus have intrinsic tigecycline resistance via upregulated efflux.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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