Protein Synthesis Inhibitors: 30S Subunit Targets

• Cytoplasmic ribosomes in animal cells (80S) are structurally different from those in bacterial cells (70S).
• This structural difference allows protein biosynthesis to be a selective target for antibacterial drugs due to the differences ribosomes.

Protein Synthesis Inhibitors Targeting 30S Subunit

• Aminoglycosides are potent broad-spectrum antibacterials that bind to the 30S subunit of bacterial ribosomes.
• Aminoglycosides impair the proofreading ability of the ribosomal complex, leading to mismatches between codons and anticodons.
• This results in the production of the faulty proteins that insert into the cytoplasmic membrane.
• These faulty proteins disrupt the cytoplasmic membrane to kill bacterial cells.
• Examples of aminoglycosides are streptomycin, gentamicin, neomycin, and kanamycin.
• Aminoglycosides can cause nephrotoxicity, neurotoxicity, and ototoxicity.
• Tetracyclines are bacteriostatic antibacterials that also bind to the 30S subunit.
• Tetracyclines inhibit protein synthesis by blocking the association of tRNAs with the ribosome during translation.
• Tetracyclines were first discovered in the 1940s from Streptomyces strains and are mainly bacteriostatic.
• Examples of tetracyclines are doxycycline and tigecycline.
• Tetracyclines are a broad spectrum antibiotic, but its side effects include phototoxicity, permanent discoloration of developing teeth, and liver toxicity.

Protein Synthesis Inhibitors Targeting 50S Subunit

• Several classes of antibacterial drugs act by binding to the 50S subunit of bacterial ribosomes.
• Macrolides are broad-spectrum, bacteriostatic drugs that inhibit peptide bond formation.
• Macrolides block elongation of proteins by inhibiting peptide bond formation between specific combinations of amino acids.
• Erythromycin was the first macrolide, it prevents translocation and was isolated in 1952 from Streptomyces erythreus.
• Examples of semisynthetic macrolides are azithromycin and telithromycin.
• Azithromycin has a broader spectrum of activity, fewer side effects, and a longer half-life (68 hours) compared to erythromycin (1.5 hours).
• Telithromycin is a ketolide showing increased potency and activity against macrolide-resistant pathogens.
• Telithromycin is limited to the treatment of community-acquired pneumonia and needs a black box warning label due to hepatotoxicity.
• Lincosamides, including lincomycin and clindamycin, have a similar mode of action to macrolides, preventing peptide bond formation by binding to the 50S ribosomal subunit.
• Lincosamides are particularly active against streptococcal and staphylococcal infections.
• Chloramphenicol is an antibacterial that binds to the 50S ribosome, inhibiting peptide bond formation.
• Chloramphenicol, produced by Streptomyces venezuelae, was the first broad-spectrum antibiotic approved by the FDA.
• Chloramphenicol had a wide range of treatment uses, but has serious side effects that limit its clinical role, such as lethal gray baby syndrome and bone marrow suppression.
• Chloramphenicol also targets mitochondrial ribosomes, causing a reversible, dose-dependent suppression of blood cell production.
• Chloramphenicol usage in humans is rare in the United States because the toxicity concerns, but the side effects are less severe in animals, so it's used in veterinary medicine.
• Oxazolidinones, like linezolid, are a new broad-spectrum class of synthetic protein synthesis inhibitors that bind to the 50S ribosomal subunit.
• They interfere with the formation of the initiation complex and prevent the translocation of the growing protein from the ribosomal A site to the P site.

Inhibitors of Membrane Function

• Polymyxins are natural polypeptide antibiotics discovered in 1947 from Bacillus polymyxa.
• Polymyxin B and polymyxin E (colistin) are used clinically.
• Polymyxins are lipophilic with detergent-like properties and disrupt the membranes of gram-negative bacteria.
• Polymyxins also damage the membranes of cells in the kidney and nervous system when administered systemically.
• Side effects and poor absorption leads to polymyxin B use topically in antibiotic ointments, while oral colistin was historically for bowel decontamination.
• Multidrug-resistant pathogens have led to increased use of intravenous colistin in hospitals.
• Daptomycin is a cyclic lipopeptide from Streptomyces roseosporus which disrupts the bacterial cell membrane.
• Daptomycin targets specifically gram-positive bacteria, unlike polymyxin B and colistin.
• Daptomycin is administered intravenously and well tolerated, showing reversible toxicity in skeletal muscles.