Antibiotics and Protein Synthesis Quiz

Introduction

• Protein synthesis inhibitors are antibiotics targeting bacterial protein synthesis processes like translation or transcription
• Cell Wall Synthesis: these antibiotics inhibit the synthesis of the bacterial cell wall
• Cell Membrane Integrity: Antibiotics like polymyxins disrupt the bacterial cell membrane, causing leakage of cell contents and cell death
• Nucleic Acid Synthesis: Antibiotics interfere with DNA and RNA synthesis, disrupting replication and transcription processes
• Metabolic Pathways: Antibiotics inhibit crucial bacterial enzymes involved in folic acid synthesis, essential for DNA and RNA synthesis
• Protein Synthesis: Antibiotics bind to bacterial ribosomes, interfering with protein synthesis, preventing the production of essential proteins for growth and reproduction

Protein Synthesis Inhibitors

• Aminoglycosides (e.g., streptomycin, gentamicin)
• Macrolides (e.g., erythromycin, clarithromycin)
• Tetracyclines (e.g., tetracycline, doxycycline)
• Chloramphenicol

Aminoglycosides

• Aminoglycosides are polycationic carbohydrates containing amino sugars in glycosidic linkages
• They are derived from soil actinomycetes of the genus Streptomyces (streptomycin, kanamycin, tobramycin, neomycin) and the genus Micromonospora (gentamicin and sisomicin) and semisyntetic products (Amikacin and netilmicin)
• Highly water-soluble, polar compounds, therefore given parenterally
• Remain extracellular and have poor penetration into the CSF
• Primarily excreted unchanged by the kidneys, mainly effective against gram-negative organisms
• Variable degrees of ototoxicity and nephrotoxicity as adverse effects
• Actively transported into the bacterial cell
• Bind irreversibly to the 30S ribosomal subunit
• Inhibit the formation of the initiation complex, cause misreading of mRNA, and lead to premature termination of protein synthesis
• Production of abnormal proteins disrupts the bacterial cell membrane, increasing permeability, leading to bacterial cell death
• Spectrum of Activity: Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter sp.), some Gram-positive bacteria (limited activity); often used in combination therapy.
• Clinical Uses: Severe systemic infections (UTIs), endocarditis (in combination with other antibiotics), intra-abdominal infections, osteomyelitis, surgical prophylaxis, pulmonary infections (e.g., inhaled tobramycin).
• Resistance: Resistance mechanisms include efflux pumps, decreased uptake, and modification/inactivation by plasmid-associated enzymes (e.g., acetyltransferases, phosphotransferases, and adenyltransferases).
• Adverse effects: ototoxicity (vestibular and auditory), nephrotoxicity (kidney damage from mild impairment to severe necrosis), neuromuscular paralysis, allergic reactions (contact dermatitis).
• Pharmacokinetics: Primarily renal excretion; relatively poor tissue penetration; variable absorption after oral administration

Tetracyclines

• Tetracyclines consist of four fused rings with a system of conjugated double bonds
• Substitutions on these rings alter the individual pharmacokinetics and spectrum of antimicrobial activity
• Mechanism of Action: Reversibly binds to 30S ribosomal subunit, preventing tRNA binding to the mRNA-ribosome complex and inhibiting protein synthesis
• Spectrum of Activity: Effective against Gram-positive bacteria (e.g., Staphylococcus aureus, Streptococcus pneumoniae); Gram-negative bacteria (e.g., Haemophilus influenzae, Helicobacter pylori); atypical organisms (e.g., Mycoplasma pneumoniae, Chlamydia spp.); Rickettsiae, Borrelia burgdorferi (Lyme disease)
• Clinical Uses: Respiratory tract infections; acne; chlamydia infections; Lyme disease; peptic ulcer disease; malaria prophylaxis and treatment.
• Absorption: Oral bioavailability is 60-80% for most; 100% for doxycycline and minocycline, reduced by food (especially dairy and calcium-rich foods)
• Distribution: Widely distributed, limited penetration into the CSF, high affinity for calcium-rich tissues, high protein binding (~90% for doxycycline and minocycline, ~60% for tetracycline).
• Excretion: Primarily renal and biliary; tetracycline: 6-12 hours; Doxycycline and minocycline: 16-24 hours
• Adverse effects: gastric discomfort, effects on calcified tissues (discoloration and hypoplasia of teeth), hepatotoxicity, phototoxicity, vestibular dysfunction, pseudotumor cerebri
• Contraindications: pregnancy (Category D); children under 8 years old

Macrolides and Ketolides

• Macrolides: a group of antibiotics with one or more deoxy sugars attached (e.g., erythromycin, azithromycin, clarithromycin, telithromycin)
• Ketolides: overcome resistance by being bacteriostatic and bactericidal. Mechanism of Action: binds to site on 50S ribosomal subunit; inhibits translocation steps of protein synthesis.
• Spectrum of Activity: Effective against Gram-positive bacteria (e.g., Staphylococcus aureus, Streptococcus pneumoniae); Gram-negative bacteria (e.g., Haemophilus influenzae, Moraxella catarrhalis); atypical pathogens (e.g., Mycoplasma pneumoniae, Chlamydia spp., Legionella spp.)
• Clinical Uses: Respiratory tract infections; skin and soft tissue infections; sexually transmitted infections; Helicobacter pylori infections; prophylaxis for bacterial endocarditis (in patients with penicillin allergies)
• Adverse effects: Nausea, vomiting, diarrhea, abdominal pain; hepatotoxicity (rare); cardiotoxicity (QT prolongation); rash; pruritus; Drug interactions (CYP3A4 inhibitors).
• Pharmacokinetics: generally well absorbed orally; affected by food; excellent tissue penetration; moderate protein binding; primarily metabolized in the liver via CYP3A4 (except azithromycin); mostly excreted in bile, some via urine

Chloramphenicol

• Broad-spectrum antibiotic restricted to life-threatening infections lacking alternatives
• Spectrum of Activity: Effective against Gram-positive and Gram-negative bacteria, and some anaerobes
• Clinical Uses: Serious infections (e.g., meningitis, typhoid fever, severe bacterial infections)
• Mechanism of Action: Binds to bacterial 50S ribosomal subunit, inhibiting peptide bond formation, preventing protein elongation, and inhibiting bacterial growth (bacteriostatic effect).
• Adverse effects: Bone marrow suppression (reversible or irreversible aplastic anemia); gray baby syndrome (in neonates due to reduced metabolism); nausea, vomiting, diarrhea, allergic reactions
• Contraindications: pregnancy (avoid unless benefits outweigh risks); neonates (risk of gray baby syndrome)

Other agents from protein synthesis inhibitor

• Quinupristin/dalfopristin: mixture of two streptogramins; synergistic action (Quinupristin binds to 50S; Dalfopristin blocks ribosome's exit tunnel). Clinical uses: complicated skin/skin structure infections (CSSSI) caused by resistant Gram-positive organisms. Adverse effect: musculoskeletal (arthralgia, myalgia), liver function (monitor enzymes). Drug interactions: CYP3A4 inhibitors
• Oxazolidinones (Linezolid and Tedizolid): synthetic oxazolidinones developed to combat gram-positive organisms. MOA: binds to bacterial 23S ribosomal RNA, inhibiting formation of the 70S initiation complex and translation of bacterial proteins. Clinical uses: infections (complicated skin and skin structure infections, nosocomial pneumonia, bacteremia); mycobacterial infections (some efficacy against drug-resistant tuberculosis). Adverse Effects: gastrointestinal upset, nausea, diarrhea, headache, rash, thrombocytopenia.
• Clindamycin: inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. Spectrum of Activity: effective against Gram-positive cocci (including MRSA) and anaerobic bacteria. Clinical uses: skin and soft tissue infections, dental infections, intra-abdominal infections, bone and joint infections, certain types of bacterial vaginosis. Alternative for patients allergic to beta-lactams