Antibacterials: Sulfonamides, Trimethoprim, and Quinolones/Fluoroquinolones Flashcards
What is the difference b/w topoisomerase I and II.
I - cuts one strand at a time of DNA
II - cuts both DNA strands
What is the mechanism of action of topoisomerase in the clevage of DNA?
Tyrosine hydroxyl attacks phosphate of DNA backbone.
Reversible reaction - enzyme is released with re-ligation.
Describe the topoisomerase structure & clevage mechanism.
N gate, DNA capture domain, B region, CAP, and C gate.
Above - order of entry of G then T strand. G is cleaved in DNA capture, and T passes through.
What are two roles that gyrases and topoisomerases can have in a cell?
- Relax, knot, unknot two DNA strands from same DNA molecule
- Connect (catenate) or separate (decatanate) two DNA strands from different DNA molecules.
What are the general uses for sulfonamides? Specific uses of the following:
G+, G-, Nocardia, Chlamycia, UTI, some enteric organisms
What is the specific use of Sulfisoxazole?
Sulfisoxazole - Broadest, simple UTI
What is the specific use of sulfadiazine?
Toxoplasma gondi in combo w/ pyrimethamine
What is the specific use of sulfadoxazine?
Plasmodium in combo w/ pyrmithamine
Triple sulfas? What three drugs constitute triple sulfa?
Gardenerella vaginalis
OR URT infections in combo with phenylpropanolamine pheniramine
Three drugs: Sulfabenzamide, sulfacetamide, sulfathiazole
What medication is used to treat Chron’s disease? Why is this one chosen?
Sulfasalazine.
Used because not absorbed in the GI = stays in lumen and metabolized by intestinal bacteria to an anti-inflammatory agent.
What two sulfonamides are used in combination? What are they used in combination with?
Sulfadoxazine
Sulfadiazine
the “d” sulfas
Used w/ pyrimethamine
What is the mechanism of action of sulfonamides?
PABA analogs - inhibit dihydropterate synthase = prevent dihydropteric acid and folate synthesis
What confers the specificity of the sulfonamides to the bacteria? How does this differ from the specificity mechanism of trimethoprim?
Sulfonamides - mammals get folate exogenously; inhibition does not affect mammal host
Trimethoprim - increased affinity for the bacterial enzyme (dihydrofolate reductase)
What is the origin of the sulfonamides? What is the significance of this and how is this compound activated?
Streptomyces PRONTOSIL. First drug active against baceria.
Activated by intestinal bacteria
What are the toxicities associated with sulfonamide use?
Hypersensitivity, steven's johnsons syndrome Nephrotoxicity & Crystalluria Hemolysis (G6PDH deficiency) Kernicterus in infants Displace drugs from albumin (warfarin)
What are 2 ways to decrease the crystallization of the sulfonamide antibiotics?
- Drink a lot of water with use
2. Conjugated sulfanilamide (PRONTOSIL activated) to an aromatic side group to increase the acidity
How does resistance develop to the sulfonamides?
- Alter the dihydropterate synthase enzyme
- Increased PABA Production (outcompete sulfonamide)
- Decrease uptake
What is the mechanism of trimethoprim? What is the advantage of tmp over sulfonamides?
Inhibits dihydrofolate reductase
better absorption and tissue distribution
What is the generic name for SMX + Trimethoprim?
BACTRIM
What are the general uses of Bactrim?
AIDS pneumocystis jirovecii
Complicated UTI
Some enteric organisms
What is the advantage of combinging SMX and Trimethoprim?
Individual are bacteriostatic
Combination is bacterioCIDAL
What are the general uses of quinolones and fluoroquinolones?
G- mostly, Limited G+, GI and UTI infrections
What is the mechanism of action of the quinolones and fluoroquinolones?
Inhibit 3 enzymes: 1. DNA gyrase 2. Bacterial topoisomerase IV 3. Mammal topoisomerase II Inhibition by preventing re-ligation step - stacks in between base pairs of sticky ends.
What fluoroquinolone can be used in patients with hepatic damage or on drugs that use the glucuronidation pathway in the liver?
Olfloxacin - has primarily renal clearance
What should no be taken with quinolones and fluoroquinolones and why?
divalent cations - chelation
heavy metals, antacids, etc.
What are the toxicities associated with quinolones and fluoroquinolones? What contraindications does this create?
Damage to growing cartilage - NOT IN PREGNANCY
Tendonitis
Myalgia, prolonged QT
GI upset, superinfection, rash, headache, dizziness
What is the drug of last resort for S. pneumoniae infections?
Monxifloxacin
What fluoroquinolone has additional side effects? What are they?
Gatifloxacin - hyperemia and hypoglycemia
What drugs are:
Quinolones
Fluoroquinolones - 2nd generation
Fluoroquinolones - 3rd generation
Quinolones: Nalidixic acid, Oxolinic acid
2nd gen: Cipro, Noro, Levo, Olf
3rd & 4th gen: Spar, Monxi, Gati, Enox
What is the advantage of using 2nd gen fluoroquinolones? What structural difference confers this added use?
Greater G- activity
Additional F atoms
What 2nd generation fluoroquinolone has the most activity? What organisms is this particularly effective against?
Ciprofloxacin
Pseudomonas and Mycoplasma
Also increased G+ activity.
