Tigecycline is a glycylcycline tetracycline derivative with activity against many tetracycline-resistant organisms. The mechanism by which glycylcycline avoids the most common tetracycline resistance mechanisms (efflux and ribosomal protection) is:

• A Tigecycline has a different chemical scaffold that does not bind the 30S ribosome and instead inhibits 50S peptide exit tunnel
• B Tigecycline is co-formulated with an efflux pump inhibitor that blocks Tet transporters
• C Tigecycline is a poor substrate for Tet efflux pumps and its bulky 9-glycylamido substituent sterically prevents ribosomal protection proteins from displacing it from the 30S ribosome ✓
• D Tigecycline gains entry via outer membrane channels different from those used by tetracycline, bypassing efflux pump recognition

Explanation

Classical tetracycline resistance occurs via two main mechanisms: (1) Tet efflux pumps (TetA, TetB, etc.) that pump tetracycline out of the bacterial cytoplasm; and (2) ribosomal protection proteins (TetM, TetO) that bind the ribosome and displace tetracycline from its 30S binding site. Tigecycline's bulky 9-glycylamido side chain at the D-ring makes it a poor substrate for most Tet efflux pumps (though it is susceptible to RND-family pumps like MexXY in Pseudomonas — explaining tigecycline's lack of activity against Pseudomonas aeruginosa). Additionally, the large substituent sterically interferes with TetM/TetO binding to the ribosome, preventing displacement of tigecycline.

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

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Written and medically reviewed by the StethoPrep medical team.