Omadacycline (a third-generation aminomethylcycline tetracycline) overcomes tetracycline resistance. Which resistance mechanism does it specifically evade?

• A Only TetA efflux pump resistance, by acting as a non-substrate due to its hydrophobic aromatic substituent
• B Enzymatic inactivation by tetracycline-modifying monooxygenases via steric hindrance of the C5 position
• C Both TetB (efflux pump) and TetM (ribosomal protection protein) mechanisms, due to its C9-aminomethyl side chain that prevents pump recognition and fits tighter in the ribosomal A-site despite Tet protein binding ✓
• D Tigecycline specifically overcomes TetM but omadacycline is inactive against TetM-positive isolates

Explanation

Omadacycline is a novel aminomethylcycline tetracycline derivative with a C9 amino methyl substituent that provides dual advantage: it evades both TetB-type efflux pumps (because its bulkier C9 modification makes it a poor substrate for pump recognition) and ribosomal protection proteins like TetM/TetO (because the aminomethyl group sterically stabilizes drug binding in the decoding A-site region of 16S rRNA, preventing displacement by Tet proteins). Like tigecycline (9-t-butylglycylamido minocycline, a glycylcycline), omadacycline overcomes TetM ribosomal protection. Unlike tigecycline, omadacycline is orally bioavailable (the first IV+oral tetracycline for CABP and ABSSSI) and is approved for both community-acquired pneumonia and acute skin infections.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.