What is the class and mechanism of action of Tigecycline (glycylcycline antibiotic)?

Tigecycline: Class and Mechanism of Action

Tigecycline is a glycylcycline antibiotic—the first in its class—that inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit and blocking aminoacyl-tRNA entry into the A site, thereby preventing amino acid incorporation into elongating peptide chains. 1, 2

Drug Classification

• Tigecycline is a semisynthetic glycylcycline, representing a new structural class derived from the tetracycline family with chemical structure similar to minocycline 1, 3
• It is the first and most extensively studied member of the glycylcycline class 4

Mechanism of Action

Ribosomal Binding and Protein Synthesis Inhibition:

• Tigecycline binds specifically to the 30S ribosomal subunit at the A site, blocking the entry of aminoacyl-tRNA molecules 2, 5
• This prevents incorporation of amino acid residues into elongating peptide chains, thereby inhibiting bacterial protein translation 2, 3
• The drug demonstrates 3-fold greater potency than minocycline and 20-fold greater potency than tetracycline in inhibiting protein synthesis 5
• Biophysical analyses show tigecycline binds to isolated ribosomes with a dissociation constant of 10⁻⁸ M, compared to 10⁻⁷ M for minocycline and >10⁻⁶ M for tetracycline 5

Structural Basis for Enhanced Activity:

• Molecular modeling places tigecycline in the A site with substantial interactions with residues of helix 34 (H34) of the 30S ribosomal subunit—interactions not observed with tetracycline binding 5
• These novel binding interactions allow tigecycline to overcome tetracycline resistance mechanisms 5

Resistance Mechanisms Overcome

Tigecycline is specifically designed to circumvent the two major tetracycline resistance mechanisms:

• Ribosomal protection proteins: The drug maintains activity despite ribosomal protection mechanisms that confer tetracycline resistance 1, 2
• Drug-specific efflux pumps: Tigecycline overcomes tetracycline-specific efflux pump acquisition 1, 2
• No cross-resistance has been observed between tigecycline and other antibacterial classes 2
• The drug is not affected by β-lactamases (including ESBLs), target-site modifications, macrolide efflux pumps, or enzyme target changes (e.g., gyrase/topoisomerases) 2

Bacteriostatic vs. Bactericidal Activity

• Tigecycline is generally bacteriostatic against most organisms 2, 6
• However, it demonstrates bactericidal activity against specific pathogens including Streptococcus pneumoniae and Legionella pneumophila 2

Clinical Caveats

Important Limitations Related to Mechanism:

• Despite strong ribosomal binding, tigecycline has a large volume of distribution (7-9 L/kg) but achieves low serum concentrations (Cmax 0.87 mcg/mL with standard dosing) 1, 3
• This pharmacokinetic profile makes it unsuitable for bacteremic infections with standard dosing, as confirmed by poor clinical outcomes in A. baumannii bacteremia 1
• Tigecycline concentrations in endothelial lining fluid are extremely low (0.01-0.02 mg/L), explaining suboptimal pulmonary efficacy 1
• Some bacteria (particularly Acinetobacter species) can develop resistance through multidrug-resistant (MDR) efflux pumps not specific to tetracyclines 2