Antibacterials: Sulfonamides, Trimethoprim, and Quinolones/Fluoroquinolones

Question 1

What is the difference b/w topoisomerase I and II.

Answer 1

I - cuts one strand at a time of DNA

II - cuts both DNA strands

Question 2

What is the mechanism of action of topoisomerase in the clevage of DNA?

Answer 2

Tyrosine hydroxyl attacks phosphate of DNA backbone.

Reversible reaction - enzyme is released with re-ligation.

Question 3

Describe the topoisomerase structure & clevage mechanism.

Answer 3

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.

Question 4

What are two roles that gyrases and topoisomerases can have in a cell?

Answer 4

1. Relax, knot, unknot two DNA strands from same DNA molecule
2. Connect (catenate) or separate (decatanate) two DNA strands from different DNA molecules.

Question 5

What are the general uses for sulfonamides? Specific uses of the following:

Answer 5

G+, G-, Nocardia, Chlamycia, UTI, some enteric organisms

Question 6

What is the specific use of Sulfisoxazole?

Answer 6

Sulfisoxazole - Broadest, simple UTI

Question 7

What is the specific use of sulfadiazine?

Answer 7

Toxoplasma gondi in combo w/ pyrimethamine

Question 8

What is the specific use of sulfadoxazine?

Answer 8

Plasmodium in combo w/ pyrmithamine

Question 9

Triple sulfas? What three drugs constitute triple sulfa?

Answer 9

Gardenerella vaginalis
OR URT infections in combo with phenylpropanolamine pheniramine

Three drugs: Sulfabenzamide, sulfacetamide, sulfathiazole

Question 10

What medication is used to treat Chron’s disease? Why is this one chosen?

Answer 10

Sulfasalazine.
Used because not absorbed in the GI = stays in lumen and metabolized by intestinal bacteria to an anti-inflammatory agent.

Question 11

What two sulfonamides are used in combination? What are they used in combination with?

Answer 11

Sulfadoxazine
Sulfadiazine
the “d” sulfas
Used w/ pyrimethamine

Question 12

What is the mechanism of action of sulfonamides?

Answer 12

PABA analogs - inhibit dihydropterate synthase = prevent dihydropteric acid and folate synthesis

Question 13

What confers the specificity of the sulfonamides to the bacteria? How does this differ from the specificity mechanism of trimethoprim?

Answer 13

Sulfonamides - mammals get folate exogenously; inhibition does not affect mammal host
Trimethoprim - increased affinity for the bacterial enzyme (dihydrofolate reductase)

Question 14

What is the origin of the sulfonamides? What is the significance of this and how is this compound activated?

Answer 14

Streptomyces PRONTOSIL. First drug active against baceria.

Activated by intestinal bacteria

Question 15

What are the toxicities associated with sulfonamide use?

Answer 15

Hypersensitivity, steven's johnsons syndrome
Nephrotoxicity & Crystalluria
Hemolysis (G6PDH deficiency)
Kernicterus in infants
Displace drugs from albumin (warfarin)

Question 16

What are 2 ways to decrease the crystallization of the sulfonamide antibiotics?

Answer 16

1. Drink a lot of water with use

2. Conjugated sulfanilamide (PRONTOSIL activated) to an aromatic side group to increase the acidity

Question 17

How does resistance develop to the sulfonamides?

Answer 17

1. Alter the dihydropterate synthase enzyme
2. Increased PABA Production (outcompete sulfonamide)
3. Decrease uptake

Question 18

What is the mechanism of trimethoprim? What is the advantage of tmp over sulfonamides?

Answer 18

Inhibits dihydrofolate reductase

better absorption and tissue distribution

Question 19

What is the generic name for SMX + Trimethoprim?

Answer 19

BACTRIM

Question 20

What are the general uses of Bactrim?

Answer 20

AIDS pneumocystis jirovecii
Complicated UTI
Some enteric organisms

Question 21

What is the advantage of combinging SMX and Trimethoprim?

Answer 21

Individual are bacteriostatic

Combination is bacterioCIDAL

Question 22

What are the general uses of quinolones and fluoroquinolones?

Answer 22

G- mostly, Limited G+, GI and UTI infrections

Question 23

What is the mechanism of action of the quinolones and fluoroquinolones?

Answer 23

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.

Question 24

What fluoroquinolone can be used in patients with hepatic damage or on drugs that use the glucuronidation pathway in the liver?

Answer 24

Olfloxacin - has primarily renal clearance

Question 25

What should no be taken with quinolones and fluoroquinolones and why?

Answer 25

divalent cations - chelation

heavy metals, antacids, etc.

Question 26

What are the toxicities associated with quinolones and fluoroquinolones? What contraindications does this create?

Answer 26

Damage to growing cartilage - NOT IN PREGNANCY
Tendonitis
Myalgia, prolonged QT
GI upset, superinfection, rash, headache, dizziness

Question 27

What is the drug of last resort for S. pneumoniae infections?

Answer 27

Monxifloxacin

Question 28

What fluoroquinolone has additional side effects? What are they?

Answer 28

Gatifloxacin - hyperemia and hypoglycemia

Question 29

What drugs are:
Quinolones
Fluoroquinolones - 2nd generation
Fluoroquinolones - 3rd generation

Answer 29

Quinolones: Nalidixic acid, Oxolinic acid
2nd gen: Cipro, Noro, Levo, Olf
3rd & 4th gen: Spar, Monxi, Gati, Enox

Question 30

What is the advantage of using 2nd gen fluoroquinolones? What structural difference confers this added use?

Answer 30

Greater G- activity

Additional F atoms

Question 31

What 2nd generation fluoroquinolone has the most activity? What organisms is this particularly effective against?

Answer 31

Ciprofloxacin
Pseudomonas and Mycoplasma
Also increased G+ activity.