Antifolates, Quinolones, & Metronidazole

Question 1

What are antimetabolites?

Answer 1

They act to block bacterial folic acid synthesis.

Question 2

What is the mechanism of action of sulfa drugs?

Answer 2

inhibit biosynthesis of purines & pyrimidines by blocking dihydropteroic acid synthetase (the enzyme that converts PABA to dihydrofolic acid)

Question 3

How does trimethoprim act with sulfa drugs?

Answer 3

blocks dihydrofolate reductase; acts synergistically

Question 4

What is the mechanism of action of fluoroquinolones?

Answer 4

inhibit bacterial DNA gyrase and topoisomerase; kill by conc-dependent effect

Question 5

What is metronidazole?

Answer 5

antiprotozoal agent; antibacterial activity against obligate anaerobes

Question 6

How do bacteria acquire and use folate for DNA, RNA, protein synthesis?

Answer 6

folate from environment (PABA) + pteridine + DHPS (dihydropteroate synthase) = dihydropteroic acid + glutamate = dihydrofolic acid + NADPH to NADP through DHFR = tetrohydofolic acid—goes to purines, thymidine, methionine

Question 7

Why are sulfonamides selectively toxic?

Answer 7

DHPS enzyme does not function in humans b/c we get our folate from our diet

Question 8

mechanisms of resistance to sulfa drugs

Answer 8

• -overproduction of PABA
• -encode mutant DHPS enzyme w/ decreased affinity for sulfas
• -upregulation of efflux pumps

Question 9

What is Kernicterus?

Answer 9

in infants, sulfa competes for bilirubin binding sites on albumin and increases levels of unconjugated bilirubin = CNS toxicity

Question 10

What makes trimethoprim more selective for bacteria?

Answer 10

affinity for bacterial DHFR is 100,000X higher than for human DHFR

Question 11

mechanisms of resistance to trimethoprim-sulfamethoxazole

Answer 11

• -overexpression of DHFR

- -expression of mutant DHFR that is resistant to trimethoprim

Question 12

mechanism of action of quinolones

Answer 12

inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, blocks DNA unwinding, induces irreversible DNA damage/degradation

Question 13

Rate the level of effectiveness of the fluoroquinolones against gram- including Pseudomonas.

Answer 13

cipro>levo>moxi

Question 14

Rate the level of effectiveness of the fluoroquinolones against gram+ including Streptococci.

Answer 14

moxi>levo>cipro

Question 15

mechanism of resistance against fluoroquinolones

Answer 15

• -spontaneous mutations
• -one pt mutation causes elevation in MIC
• -mutations in both gyrase & topoisomerase genes cause high resistance
• *nearly all MRSA resistant (hospital cipro use)