30.05.2025 – Britain.
Introduction:
Antibiotics are pivotal agents in the treatment and prevention of bacterial infections. Their discovery marked a turning point in medical history, reducing death rates from formerly lethal diseases. However, with increasing microbial resistance, the importance of a nuanced understanding of antibiotic mechanisms and judicious clinical application has become more critical than ever.
Classification Based on Mechanism of Action
Antibiotics exert their effects through distinct mechanisms targeting essential bacterial processes. The primary mechanisms include:
Inhibition of Cell Wall Synthesis Bacteria possess a rigid cell wall composed mainly of peptidoglycan, which is essential for maintaining structural integrity and survival in hypotonic environments.
Beta-Lactams (Penicillins, Cephalosporins, Carbapenems, Monobactams): These antibiotics bind to penicillin-binding proteins (PBPs), enzymes involved in the final stages of peptidoglycan cross-linking. This leads to cell lysis due to osmotic instability.
Clinical relevance: Highly effective against Gram-positive cocci; resistance mediated via beta-lactamase enzymes or PBP alterations (e.g., MRSA).
Glycopeptides (Vancomycin, Teicoplanin): Inhibit cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan precursors, preventing incorporation into the cell wall.
Clinical relevance: Primarily active against Gram-positive organisms, including MRSA; not effective against Gram-negatives due to poor outer membrane penetration.
Inhibition of Protein Synthesis Protein synthesis is essential for bacterial survival and involves 30S and 50S ribosomal subunits.
Aminoglycosides (Gentamicin, Amikacin): Bind irreversibly to the 30S subunit, causing misreading of mRNA and premature termination of translation.
Clinical relevance: Bactericidal; used in severe Gram-negative infections; nephrotoxic and ototoxic.
Tetracyclines (Doxycycline, Tetracycline): Bind reversibly to the 30S subunit, preventing tRNA attachment.
Clinical relevance: Broad-spectrum, including atypical pathogens; contraindicated in pregnancy and children due to bone/teeth effects.
Macrolides (Azithromycin, Erythromycin): Bind to the 50S subunit, inhibiting translocation of peptidyl-tRNA.
Clinical relevance: Used in respiratory tract infections; an alternative in penicillin allergy.
Clindamycin (Lincosamide): Also binds 50S subunit; useful against anaerobes and Gram-positive cocci.
Chloramphenicol and Linezolid: Broad-spectrum; Linezolid inhibits the initiation complex, effective against resistant Gram-positive bacteria.
Inhibition of Nucleic Acid Synthesis
Fluoroquinolones (Ciprofloxacin, Levofloxacin): Inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, enzymes critical for DNA replication.
Clinical relevance: Broad-spectrum; used in UTIs, GI infections; risk of tendon rupture and QT prolongation.
Rifamycins (Rifampin): Inhibits DNA-dependent RNA polymerase.
Clinical relevance: Key in TB treatment; induces cytochrome P450 enzymes.
Metronidazole: Forms toxic radicals in anaerobic cells, damaging DNA.
Clinical relevance: Effective against anaerobes and protozoa; disulfiram-like reaction with alcohol.
Antimetabolites (Folate Pathway Inhibitors)
Sulfonamides and Trimethoprim: Sulfonamides inhibit dihydropteroate synthase, and trimethoprim inhibits dihydrofolate reductase.
Clinical relevance: Combined as co-trimoxazole; used in UTIs, Pneumocystis jirovecii pneumonia; hypersensitivity reactions are common.
Disruption of Cell Membrane Integrity
Polymyxins (Polymyxin B, Colistin): Disrupt bacterial outer membranes by interacting with lipopolysaccharides.
Clinical relevance: Reserved for multidrug-resistant Gram-negative infections; nephrotoxic.
Daptomycin: Inserts into Gram-positive membranes in a calcium-dependent manner, causing depolarization.
Clinical relevance: Not used in pneumonia; inactivated by surfactant.
Mechanisms of Resistance Resistance mechanisms include:
Enzymatic degradation (e.g., beta-lactamases)
Altered target sites (e.g., mutated PBPs, methylated ribosomes)
Efflux pumps
Reduced permeability
Conclusion:
A deep understanding of antibiotic mechanisms and resistance patterns is essential for effective therapy and stewardship. Proper usage informed by pharmacology, microbiology, and clinical judgment remains the cornerstone in combating infectious diseases and preventing the spread of antimicrobial resistance.
– Eelaththu Nilavan.
24/05/2025.
