Antibiotics-DNA and RNA Biogenesis Inhibitors Flashcards
What are the major DNA/RNA biogenesis inhibitors?
1) Anti-folates: Trimethoprim/Sulfa (TMP/SMX)
2) DNA Gyrase Inhibitors - Fluoroquinolones: Ciprofloxacin, Levofloxacin, Moxifloxacin
3) DNA Alkylator: Metronidazole
4) RNA Polymerase Inhibitors - Rifamycins: Rifampin
Why is folate needed for DNA biosynthesis?
Folate derivatives serve as sources of carbon atoms in the following reactions:
1) dUMP –> dTMP
2) Formation of purine aromatic ring
What are anti-folates?
- Dihydropteorate Syntase (DHPS) inhibitors
- Analog of PABA - competitive inhibitor of dihydropteorate synthase
What is the main DHPS inhibitor anti-folate?
Sulfamethoxazole (SMX)
What drug is SMX often combined with?
Most common use – in combination with DHFR inhibitor trimethoprim
*together => Bactrim
- Never use in life threatening situations
What is trimethroprim?
- Competitive inhibitor of DHFR
- TMP is 50,000 times more active against the bacterial DHFR vs mammalian DHFR
What are the major side effects of trimethroprim?
- Allergy: Erythema multiforme & skin rashes
- Bone marrow suppression - WBC & platelets
- GI upsets N/V
- Hepatitis
- Hyperkalemia - high doses and in the elderly
*Avoid in first trimester of pregnancy (because it is an antifolate and pregnant women NEED folate)
What is ciprofloxacin?
DNA replication inhibitor => Fluoroquinolone
What is the target of fluoroquinolones to inhibit DNA replication?
Fluoroquinolones inhibit DNA gyrase (which is responsible for uncoiling the DNA)
What is the mechanism of DNA gyrase?
- Binds DNA
- Cleaves both strands with formation of the covalent complex
- Passes strands against each other
- Ligates
What is the mechanism of DNA gyrase inhibitors (fluoroquinolones)?
- Irreversibly bind to DNA/enzyme complexes, intercalating in DNA
- Replication cannot proceed through these complexes
How does fluoroquinolone resistance develop?
- Reduced DNA topoisomerase II and IV binding due to mutations
- Impaired permeability and increased drug efflux
- Protection of DNA gyrase by Qnr proteins (plasmid-mediated, new!)
- Modification by AG-acetyl transferase (plasmid-mediated, new!)
Describe the spectrum of the fluoroquinolones.
BACTERICIDAL
- Ciprofloxacin:
- Poor gram +ve (resistance rapidly acquired)
- Good gram –ve (Pseudomonas, E.coli, etc.)
- Legionella (& Mycobacteria avium intracellulare)
- Moxi- and levofloxacins:
- Wide spectrum
- Active vs gram +ve & gram –ve
+ Chlamydia
What are the clinical uses of ciprofloxacin?
Ciprofloxacin: UTI, STD
What are the clinical uses of moxi- and levofloxacin?
Moxi- and levo-: pneumonia
What is the clinical use of levofloxacin?
Levo: UTI
What is metronidazole?
DNA damaging agent
What is the mechanism of metronidazole?
- Reduced by the bacterial (anaerobes) nitroreductase
- Forms a reactive nitro - anion and radicals
- In anaerobic environment -nitro-anion and radicals interacts with DNA to form single strand breaks mainly at (A-T) base pairs
*Radicals may also damage proteins and lipids
What is the spectrum of metronidazole?
BACTERICIDAL
- Oral and bowel anaerobes (100% B. Fragilis)
- Cl. Difficile
- Protozoa (Giardia Lamblia, Entamoeba Histolytica)
What are the side effects of metronidazole?
TERATOGENIC
- GI upsets
- Metallic taste in mouth
- CNS effects- ataxia, vertigo
- Neutropenia
- Colors urine - dark
- Drug interactions; inhibits CYP3A
What are the rifamycins?
- Rifampycins -structurally complex macrocyclic inhibitors produced by Streptomyces mediteranei; RNA polymerase inhibitors
- Rifampin - is a semi-synthetic derivative of rifamycin B
What is the mechanism of rifamycins?
- Binds to the beta subunit of DNA directed bacterial RNA polymerase
- Inhibits further nascent RNA production
Describe the selectivity of rifampin.
- Does not inhibit mammalian nuclear RNA polymerase
- Inhibits mammalian mitochondrial RNA polymerase at much higher concentrations
What is the coverage of rifampin?
- Broad spectrum: most gram positives and many gram negatives
- Myco TB & other mycobacteria (static)
- Staph. Aureus (cidal)
- Legionella
- Neisseria meningitidis prophylaxis
- Active against intracellular organisms
How does bacterial resistance against rifampin develop?
- Mutations of beta subunit binding site of the RNA polymerase (rpoB gene product)
- Increasing problem in Myco. TB therapy;never use alone
