Inhibitors of Nucleic Acid Synthesis

Study Notes

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)

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

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

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

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

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