Drugs to Treat Infections

• Cell wall inhibitors in the treatment of infections:

  • Mechanism of action: inhibit cell wall synthesis
  • Examples: Penicillins, Cephalosporins, Carbapenems, Monobactams, Glycopeptides
  • Penicillins: e.g., Penicillin G (benzylpenicillin), Penicillin V, Methicillin, Ampicillin, Amoxicillin
  • Cephalosporins: e.g., Cephamycins, five separate generations recognized
  • Actions of β-lactams: act as a mimetic of Ala-Ala, irreversibly inhibit transpeptidase, prevent cell wall crosslinking, lead to increased secretion of lipoteichoic acid which inhibits autolysin, uninhibited autolysin leads to lysis of bacteria
  • Adverse effects of β-lactams: very low toxicity, may cause diarrhea, seizures (rare), allergic reactions in 2% of patients, nephrotoxicity with 1st gen cephalosporin
• Mechanism of action and resistance of protein synthesis inhibitors:

  • Bacteriostatic drugs
  • Five classes: Aminoglycosides, Macrolides, Tetracyclines, Amphenicols, Oxazolidinones
  • All inhibit ribosome complex formation
  • Aminoglycosides & tetracyclines bind to 30S
  • Macrolides, linezolid & streptogramins bind to 50S
  • Prokaryotic ribosomes are 70S with subunits 30S and 50S
  • 30S ribosome has 16S RNA, 50S ribosome contains 23S and 5
• Mechanism of action and resistance of nucleic acid inhibitors
• Anti-microbial resistance mechanisms:

  • Enzymatic degradation
  • Mutations in drug target
  • Reduced permeability, especially in Gram-negative bacteria
  • Xenobiotic pumps: MexB (β-lactams), MexY (aminoglycosides) in Gram-negative bacteria
• Development of antibiotic resistance:

  • Nature Chemical Biology 3, 541 - 548 (2007)
  • Mechanisms like enzymatic degradation, mutations in drug targets, and reduced permeability contribute to antibiotic resistance
• Macrolides, Tetracyclines, Amphenicols, and Oxazolidinones all inhibit ribosome complex formation
• Aminoglycosides and tetracyclines bind to the 30S ribosomal subunit
• Prokaryotic ribosomes consist of 70S subunits, with 30S ribosome containing 16S RNA and 50S ribosome containing 23S and 5S RNA
• Aminoglycosides, like streptomycin, bind to the 30S ribosomal subunit, enter cells using an oxygen-dependent transporter system, and are nephrotoxic and ototoxic
• Tetracyclines, such as tetracycline and doxycycline, bind to the 30S ribosomal subunit, are orally active, and can cause teeth staining and photosensitivity
• Macrolides, like azithromycin and erythromycin, bind to the 50S ribosomal subunit, are orally active, and are used for respiratory infections
• Streptogramins, such as quinupristin and dalfopristin, are used in combination, bind to distinct sites on the 50S subunit, and have a synergistic effect
• Oxazolidinones, like linezolid, bind to the 50S ribosomal subunit, have good tissue penetration, and can cause myelosuppression
• Daptomycin is a cyclic lipopeptide that binds to bacterial membranes causing depolarization, while telavancin is a lipoglycopeptide active against aerobic Gram-positive organisms
• Inhibitors of DNA synthesis include quinolones and fluoroquinolones, like ciprofloxacin, which inhibit DNA gyrase and topoisomerase IV
• Rifamycins, such as rifampin, rifabutin, and rifapentine, inhibit DNA-dependent RNA polymerase and are important in the treatment of tuberculosis
• Isoniazid inhibits the synthesis of mycolic acids, ethambutol inhibits polymerization of arabinogalactan, and pyrazinamide inhibits the synthesis of short-chain fatty acid precursors in anti-tuberculosis therapy
• Antibiotic therapy can disrupt gut microflora, leading to increased monosaccharides and facilitating the growth of pathogens like Salmonella and Clostridium difficile