Mechanism of actions - Exam 2

Question 1

Chloroquine

Answer 1

accumulates in food vacuole of plasmodium and prevents polymerization of the hemoglobin breakdown product heme into hemozoin

Heme is toxic to the parasite

Resistance can develop to this by having pumps to shuttle the drug out

Question 2

Quinine

Answer 2

complexes with dsDNA to prevent strand separation, resulting in a block of DNA replication and transcription to RNA

NOTE: IUSM TEACHER SAYS THAT MECH UNKNOWN, BUT PROB SIMILAR TO CHLOROQUINE

Question 3

Primaquine

Answer 3

orms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants — ROS

Question 4

Antifolates

Answer 4

Ultimately inhibit the production of DNA/RNA synthesis

Question 5

Sulfonamides

Answer 5

act as antimetabolites of PABA and block folic acid synthesis by inhibiting DIHYDROPTEROATE SYNTHESIS

Question 6

Pyrimethamine

Answer 6

selective inhibitor of protozoan dihydrofolate reductase

Question 7

Proguanil (part of malarone?)

Answer 7

bioactivated to cycloguanil which is a selective inhibitor of protozoan dihydrofolate reductase

Question 8

Amodiaquine

Answer 8

component of malarone

disrupts mitochondrial electron transport in protozoa

Question 9

Artemisinin and its derivatives

Answer 9

metabolized in the food vacuole of the parasite, forming toxic free radicals

Question 10

Metronidazole and tinidazole

Answer 10

not definitively known - Katzung says it undergoes a reductive bioactivation of its nitrogroup by ferredoxin to form reactive cytotoxic products

METRONIDAZOLE INTERACTS WITH ALCOHOL IN THAT ACETALDEHYDE ACCUMULATES

Question 11

Benzimidazole

–which drugs are in this class?

Answer 11

binds tubulin - inhibits the polymerization of microtubules

Albendazole
Mebendazole
Thiabendatzole

Question 12

Ivermectin

Why this this selective?

Answer 12

intensified GABA-mediated neurotransmission; paralyzes microfilariae; faciliates microfiliare removal by RES via cytotoxic cells (allows them to adhere)

selective b/c it doesn’t cross BBB

Question 13

Pyrantel pamoate

Answer 13

stimulates nicotinic receptors present in NMJ of nematodes - neuromuscular blocking agent; causes realease of Ach and inhibition of cholinesterase; worms are paralyzed and expelled

Question 14

Praziquantel

Answer 14

increases membrane permeability to calcium, causing marked contraction initially and then paralysis of trematode and cestode muscles (…but IUSM teacher also said it is used for nematodes)

Question 15

Penicillins

Answer 15

Beta-lactam antibiotics inhibit transpeptidases that “glue” the peptidoglycan strands together by cross-linking (transpeptidase that cross-links the peptidoglycan strands)

Katzung:

1. Binding of the drug to specific enzymes (penicillin-binding proteins) in bacterial cytoplasmic membrane
2. Inhibition of transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall
3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall

Question 16

Vancomycin

Answer 16

Inhibits Gram+ cell wall synthesis

binds to peptidyl side change D-ala-D-ala terminus in the peptidoglycan precursor (before cross-linking)

Note: similar result as with B-lactams, but different mechanisms

Question 17

What drugs inhibit microbial protein synthesis?

Answer 17

1. Chloramphenicol
2. Tetracycline
3. Macrolides
4. Telithromycin
5. Clindamycin
6. Streptogramins
7. Linezolid

Question 18

Macrolides

Answer 18

inhibit protein synthesis by binding reversibly to the P site of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA from the A site to the P site (inhibit transpeptidation)

mainly invovles binding to 23S RNA, NOT the ribosomal protein

Question 19

Aminoglycosides

Answer 19

KATZUNG: Bind to the 30S ribosome and interfere with protein synthesis in at least 3 ways
○ Block formation of the initiation complex
○ Cause misreading of the code on the mRNA template
○ Inhibit translocation

CUSHMAN: binds to 30 ribosomal subunit, specifically the 16S rRNA forming the A site
○ Interferes with formation of the initiation complex, blocks further translation, and elicits premature termination
○ Impairs proofreading function
○ Selection of wrong aminoacids during translation causes formation of “nonsense proteins”

Question 20

Examples of aminoglycosides

Answer 20

Kanamycin A
Gentamycin
Streptomycin

Question 21

Streptogramins

Answer 21

Quinupristin - binds to the ribosomal tunnel and causes blockage of the tunnel

Dalfopristin - directly interferes with the peptidyl trasnferase-catalyzed step in peptide synthesis

Synercid = Quinupristin (30%) + Dalfopristin (70%)

Question 22

Clindamycin

Answer 22

Similar to that of the macrolide antibiotics like erythromycin

It inhibits protein synthesis by binding to the bacterial 50S ribosome (It binds to the same site as erythromycin)

Antagonism and cross-resistance between clindamycin and erythromycin have been reported

Question 23

Tetracycline

Answer 23

Bind to the 30S ribosomal subunit and inhibit bacterial protein synthesis by blocking the attachment of the aminoacyl-tRNA to the A site of the ribosome, resulting in termination of peptide chain growth. More precisely, they are inhibitors of the codon-anticodon interaction.

Question 24

Chloramphenicol

Answer 24

Binds reversibly to the 50S ribosomal subunit at a site that is near the site for erythromycin and clindamycin (competitive binding interactions occur among these drugs)

It inhibits the peptidyl transferase activity of the ribosome and thus blocks peptide bond formation between the P site and the A site

Question 25

Linezolid (an oxazolidinone)

Answer 25

interacts with the 23S rRNA of the 50S ribosome

prevents the formation of the initiation complex

Question 26

Trimethamine

Answer 26

Inhibits dihydrofolate reductase

Question 27

Quinolones

Answer 27

Interfere with bacterial DNA synthesis by inhibiting topoisomerase II — this blocks DNA religation

Question 28

What do B-lactams do?

Answer 28

Acylate the transpeptidase Ser residue in the enzyme active site to form a stable product

inhibits peptidoglycan cross linking –> bacterial cell wall

cell wall subject to osmotic stress