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Block 5 Drugs > Antibiotics-DNA and RNA Biogenesis Inhibitors > Flashcards

Antibiotics-DNA and RNA Biogenesis Inhibitors Flashcards

1
Q

What are the major DNA/RNA biogenesis inhibitors?

A

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

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2
Q

Why is folate needed for DNA biosynthesis?

A

Folate derivatives serve as sources of carbon atoms in the following reactions:

1) dUMP –> dTMP
2) Formation of purine aromatic ring

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3
Q

What are anti-folates?

A
  • Dihydropteorate Syntase (DHPS) inhibitors

- Analog of PABA - competitive inhibitor of dihydropteorate synthase

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4
Q

What is the main DHPS inhibitor anti-folate?

A

Sulfamethoxazole (SMX)

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5
Q

What drug is SMX often combined with?

A

Most common use – in combination with DHFR inhibitor trimethoprim
*together => Bactrim

  • Never use in life threatening situations
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6
Q

What is trimethroprim?

A
  • Competitive inhibitor of DHFR

- TMP is 50,000 times more active against the bacterial DHFR vs mammalian DHFR

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7
Q

What are the major side effects of trimethroprim?

A
  • 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)

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8
Q

What is ciprofloxacin?

A

DNA replication inhibitor => Fluoroquinolone

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9
Q

What is the target of fluoroquinolones to inhibit DNA replication?

A

Fluoroquinolones inhibit DNA gyrase (which is responsible for uncoiling the DNA)

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10
Q

What is the mechanism of DNA gyrase?

A
  • Binds DNA
  • Cleaves both strands with formation of the covalent complex
  • Passes strands against each other
  • Ligates
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11
Q

What is the mechanism of DNA gyrase inhibitors (fluoroquinolones)?

A
  • Irreversibly bind to DNA/enzyme complexes, intercalating in DNA
  • Replication cannot proceed through these complexes
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12
Q

How does fluoroquinolone resistance develop?

A
  • 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!)
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13
Q

Describe the spectrum of the fluoroquinolones.

A

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
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14
Q

What are the clinical uses of ciprofloxacin?

A

Ciprofloxacin: UTI, STD

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15
Q

What are the clinical uses of moxi- and levofloxacin?

A

Moxi- and levo-: pneumonia

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16
Q

What is the clinical use of levofloxacin?

A

Levo: UTI

17
Q

What is metronidazole?

A

DNA damaging agent

18
Q

What is the mechanism of metronidazole?

A
  • 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

19
Q

What is the spectrum of metronidazole?

A

BACTERICIDAL

  • Oral and bowel anaerobes (100% B. Fragilis)
  • Cl. Difficile
  • Protozoa (Giardia Lamblia, Entamoeba Histolytica)
20
Q

What are the side effects of metronidazole?

A

TERATOGENIC

  • GI upsets
  • Metallic taste in mouth
  • CNS effects- ataxia, vertigo
  • Neutropenia
  • Colors urine - dark
  • Drug interactions; inhibits CYP3A
21
Q

What are the rifamycins?

A
  • Rifampycins -structurally complex macrocyclic inhibitors produced by Streptomyces mediteranei; RNA polymerase inhibitors
  • Rifampin - is a semi-synthetic derivative of rifamycin B
22
Q

What is the mechanism of rifamycins?

A
  • Binds to the beta subunit of DNA directed bacterial RNA polymerase
  • Inhibits further nascent RNA production
23
Q

Describe the selectivity of rifampin.

A
  • Does not inhibit mammalian nuclear RNA polymerase

- Inhibits mammalian mitochondrial RNA polymerase at much higher concentrations

24
Q

What is the coverage of rifampin?

A
  • 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
25
Q

How does bacterial resistance against rifampin develop?

A
  • Mutations of beta subunit binding site of the RNA polymerase (rpoB gene product)
  • Increasing problem in Myco. TB therapy;never use alone

Block 5 Drugs (9 decks)

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