Inhibitors of Nucleic Acid Synthesis

Inhibitors of Nucleic Acid Synthesis

• Rifamycin: inhibits RNA synthesis and is used to treat tuberculosis
• Quinolones and fluoroquinolones:
• Ciprofloxacin: inhibits DNA gyrase, used to treat urinary tract infections
• Mechanism of action: inhibits DNA gyrase enzyme, which unwinds double-stranded DNA, leading to inhibition of DNA replication
• Therapeutic uses:
  • Typhoid fever
  • Urinary tract infections (Gram-negative bacilli) and prostatitis
  • Gonorrhea (ofloxacin single dose)
  • Respiratory tract infections not responding to β-lactam antibiotics
  • Bone and soft tissue infections
• Adverse effects and contraindications:
  • CNS symptoms (headache, dizziness, phototoxicity)
  • Nephrotoxicity
  • Arthropathy in children less than 18 years
  • Inhibits liver microsomal enzymes, leading to drug interactions (increased level of theophylline and warfarin)

Rifampicin

• Mechanism of action: inhibits DNA-dependent RNA polymerase in mycobacteria, leading to inhibition of RNA synthesis
• Therapeutic uses:
• Potent bactericidal drug against mycobacteria tuberculosis at all sites
• Treatment of leprosy
• Prophylaxis of meningitis
• Oxacillin-resistant Staph aureus
• Adverse effects:
• Skin rash, fever, and gastrointestinal upset
• Liver damage and jaundice
• Enzyme induction, leading to serious drug interactions

Mechanisms of Antimicrobial Action

• Classification based on mechanisms of antimicrobial action
• Bacteria have their own enzymes for:
• Cell wall formation
• Protein synthesis
• DNA replication
• RNA synthesis
• Synthesis of essential metabolites
• Viruses use host enzymes inside host cells
• Fungi and protozoa have their own eukaryotic enzymes
• The more similar the pathogen and host enzymes, the more side effects the antimicrobials will have

Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis

Penicillins

• Mechanism of action: bactericidal by inhibiting transpeptidation (last step in bacterial cell wall synthesis) through binding to penicillin-binding proteins (PBP)
• β-Lactamase is an enzyme secreted by some bacteria, leading to inactivation of β-lactam antibiotics (resistance developed)
• Preparations of penicillins:
• Natural penicillins (e.g. penicillin G and penicillin V)
• Anti-staph penicillins (e.g. oxacillin, cloxacillin, and flucloxacillin)
• Extended-spectrum penicillins (e.g. ampicillin and amoxicillin)
• Antipseudomonal penicillins (e.g. ticarcillin and carbenicillin)
• Therapeutic uses:
• Streptococcal infections (e.g. acute tonsillitis, wound sepsis, puerperal sepsis, and subacute bacterial endocarditis)
• Staphylococcal infections
• Pneumococcal infections
• An influenzae-like syndrome (malaise, headache, and fever)
• Red discoloration of the urine, tears, and sputum
• Resistance rapid due to modification

Competitive Inhibitors: Sulfonamides (Sulfa drugs)

• Inhibit folic acid synthesis
• Broad spectrum
• Mechanism of action: sulfonamides are structural analogues of PABA, competing with it for the enzyme dihydropteroate synthetase, leading to inhibition of folic acid synthesis with consequent inhibition of DNA and RNA synthesis
• Therapeutic uses:
• Eye infection (topical sulfacetamide)
• Burns (topical silver sulfadiazine)
• Ulcerative colitis (sulfasalazine)
• Malaria (sulfadoxine combined with pyrimethamine)
• Adverse effects:
• Hypersensitivity reactions
• Crystalluria and nephrotoxicity due to insoluble metabolite precipitation and can be avoided by increased fluid intake and alkalinization of urine
• Hemopoietic disturbances (e.g. granulocytopenia, thrombocytopenia, and hemolytic anemia in patients with G6PD deficiency)
• Kernicterus as sulfonamides displace bilirubin from plasma protein → cross BBB in premature infants → CNS depression
• Drug interaction as it increases plasma level of oral hypoglycemic and anticoagulants due to plasma protein displacement

Trimethoprim

• Mechanism of action: inhibits dihydrofolate reductase, which converts folic acid into folinic acid (tetrahydrofolic acid), essential for DNA synthesis
• Combined with sulfamethoxazole to form co-trimoxazole
• Adverse effects:
• Megaloblastic anemia due to folate deficiency, avoided by folinic acid administration
• Granulocytopenia and leucopenia

This quiz covers inhibitors of nucleic acid synthesis, including Rifamycin and Quinolones/Fluoroquinolones, their mechanisms of action, and applications in treating diseases such as tuberculosis and urinary tract infections.