Antibiotics-DNA and RNA Biogenesis Inhibitors Flashcards Preview

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Flashcards in Antibiotics-DNA and RNA Biogenesis Inhibitors Deck (25)
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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


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.


- 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?


- Oral and bowel anaerobes (100% B. Fragilis)
- Cl. Difficile
- Protozoa (Giardia Lamblia, Entamoeba Histolytica)


What are the side effects of metronidazole?


-GI upsets
-Metallic taste in mouth
-CNS effects- ataxia, vertigo
-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