Antibiotics Mechanisms

Antibiotics are medicines that target bacteria through specific mechanisms of action. Understanding these mechanisms is vital for safe prescribing, preventing resistance, and appreciating why certain drugs work against specific organisms.

🔬 Introduction

• Antibiotics exploit structural and metabolic differences between bacteria and human cells.
• Major mechanisms include: cell wall synthesis inhibition, protein synthesis inhibition, nucleic acid disruption, metabolic blockade, and cell membrane damage.
• Knowledge of these helps clinicians predict spectrum of activity, side effects, and resistance patterns.

🧱 1. Inhibition of Cell Wall Synthesis

• β-lactams (penicillins, cephalosporins, carbapenems): Bind to penicillin-binding proteins (PBPs) → prevent cross-linking of peptidoglycan → bacterial lysis.
• Glycopeptides (vancomycin, teicoplanin): Bind D-Ala-D-Ala residues of peptidoglycan → block elongation and cross-linking.
• 💡 Clinical note: Bactericidal, best against rapidly dividing Gram-positive organisms.
• ⚠️ Resistance: β-lactamase enzymes, altered PBPs (e.g. MRSA).

🎧 2. Inhibition of Protein Synthesis

These target bacterial ribosomes (70S) which differ from human ribosomes (80S).

• Aminoglycosides (gentamicin, amikacin): Irreversibly bind 30S subunit → misreading of mRNA → defective proteins (bactericidal).
• Tetracyclines (doxycycline): Block tRNA binding at 30S subunit → prevent protein elongation (bacteriostatic).
• Macrolides (erythromycin, azithromycin, clarithromycin): Bind 50S → block translocation step (bacteriostatic).
• Chloramphenicol: Binds 50S → inhibits peptidyl transferase activity.
• Linezolid: Prevents formation of 70S initiation complex (useful against MRSA, VRE).
• 💡 Clinical note: Protein synthesis inhibitors often cause GI upset or QT prolongation (macrolides).

🧬 3. Inhibition of Nucleic Acid Synthesis

• Fluoroquinolones (ciprofloxacin, levofloxacin): Inhibit DNA gyrase & topoisomerase IV → block DNA replication.
• Rifamycins (rifampicin): Inhibit bacterial RNA polymerase → prevent transcription.
• Metronidazole: Reduced inside anaerobes to free radicals → cause DNA strand breaks.
• 💡 Clinical note: Rifampicin induces liver enzymes → drug interactions; metronidazole causes disulfiram-like reaction with alcohol.

⚡ 4. Metabolic Pathway Inhibition

• Trimethoprim: Inhibits dihydrofolate reductase → blocks folate metabolism.
• Sulfonamides (sulfamethoxazole): Inhibit dihydropteroate synthase → block earlier step in folate synthesis.
• 💊 Used in combination (co-trimoxazole) for synergy and to reduce resistance.
• 💡 Human cells use exogenous folate → not affected.

🧯 5. Disruption of Cell Membrane Function

• Polymyxins (colistin, polymyxin B): Cationic detergents that disrupt Gram-negative bacterial membranes.
• Daptomycin: Inserts into Gram-positive cell membranes, causing depolarization and cell death.
• ⚠️ Toxicity: nephrotoxicity, neurotoxicity (polymyxins); myopathy (daptomycin).

📊 Clinical Pearls

• Always match mechanism to bug (e.g., vancomycin only works on Gram-positive organisms because it can’t cross Gram-negative outer membrane).
• Understanding mechanism predicts side effects: aminoglycosides → ototoxicity, tetracyclines → teeth staining, fluoroquinolones → tendon rupture.
• Combining antibiotics with different mechanisms can be synergistic (e.g., β-lactam + aminoglycoside in endocarditis).

📚 References

• British National Formulary (BNF)
• NCBI: Mechanisms of Antibiotics
• UpToDate – Antibiotics