Aminoglycosides (MC) - Block 2

Question 1

What is the pharmacophore of aminoglycosides?

Answer 1

1-3 diaminoinositol in sugars

Question 2

What are the properties of AG?

Answer 2

Not absorbet significantly in GIT:
* Acetal unstable to stomach acid
* Too hydrophilic -> doesn’t cross membranes (GI, CNS), free water soluble at all pHs, excreted in active form

Broad antimicrobial spectra
Strongly basic

Question 3

MOA of aminoglycosides?

Answer 3

1. Bind to the 16S rRNA portion of 30S ribosomal subparticles
2. Imparis proofreading of the ribosome
3. Causes confomrational change on the peptidyl A site:
   * Leads to mistranslation of RNA templates
   * Selection of wrong amino acids and formation of nonsense proteins

Unnatural proteins -> upsetting bacterial membrane function

Question 4

How do AG disrupt bacterial membrane?

Answer 4

Destroys the semipermeability of the membrane:
1. Damge can’t be repaired without de novo programmed protein biosynthesis
2. Affords entrnce of damaging particles includig additional aminoglycoside

Question 5

How do AG enter the cell if they are polar?

Answer 5

1. Bind to external lipopolysacc and diffuse into the cells in small amounts
2. UPtake is inhibited by Ca2+ and Mg2+ ions
3. Ions are partially incompatible therapeutically

Question 6

What is the purpose of AG binding to 16S site?

Answer 6

1. Shuts down protein synthesis
2. Formation of nonsense protein
3. Formation of incomplete protein

Question 7

Activity of AG?

Answer 7

Bacteriocidal for G- (diffuses through porins passiely):
* Actively transported across cytoplasmic membrane

Not good for G+

Question 8

AG resistnce?

Answer 8

AG modifying enzymes causing bacterial inactivation:
1. Plasmid encoded enzymes that covalently modify funtionall groups and prevent drug’s ribosomal interaction
2. Point mutation of ribosomes
3. Decreased cellular uptake

Question 9

What are the covalent modifications that result in resistance?

Answer 9

1. Phsophorylation
2. Acetylation
3. Nucleotidylation (Adenylation)

Question 10

Hypothesis of resistance mechanisms?

Answer 10

AMEs bind AG with a similar conformation (1,3-diamine)

Question 11

How does amikacin bypass resistance?

Answer 11

Contains 4-amino-2-HABA attacked to N-1 of kanamycin:
* Added functional group is not on the site of all enzyme modification
* Thought to transform the entire aminogycoside into poor substrate

Question 12

What is the purpose for HABA functional group?

Answer 12

Provides incognition to the rest of the drug

Question 13

AG spectrum of activity?

Answer 13

ESKAPE and SPACE pathogens

Question 14

ADR of AG?

Answer 14

Ototoxicity: Hearing loss and vertigo by damaging of the sensory cells of innr ear:
* Mitochanidrias of the hair cells in the inner ear are destroyed

Curare like neuromuscular blockade
Nephrotoxicity: accumulation of aminoglycoside in proximal tubular cells

Question 15

What is the source of instability of streptomycin?

Answer 15

a-hydroxylaldehyde

Question 16

What is the source of kanamycin instability?

Answer 16

Gets O-phosphorylated enzymes APH(3’)-I and APH(3’)-II

Question 17

Describe the structure amikacin?

Answer 17

L-HABA attached to N-3
* Not located at the site of transformation -> decrease overall binding to the R factor mediated enzymes
* Isn’t suspectibel to modification of enzymes

Question 18

Strcture of tobarmycin?

Answer 18

1. Lacks C3’ hydroxyl group
2. Not a substrate for APH(3’) or APH(3’)-II

Gent resistant P. aeruginosa

Question 19

Enzymes of AG metabolism?

Answer 19

1. Acetylation (aminoacetyle tranferases)
2. Phosphorylation (phospho transferase)
3. Adenylation (nucleotidyl transferase)

Question 20

Structure of gentamycin?

Answer 20

1. :acks functional groups that serve as targets for R facotr enzymes
2. Inactivated through c-2’ adenylation and acetylation C6’, C1 and C2’

Question 21

What ABX is incompatible with beta lactams? Why?

Answer 21

Gentamicin:
1. They react with one another so that N-acetylation on C1 of gentamicin by the b-lactam ABX takes place
* Inactivates both ABX
* Should not be mixed n same solution
* Admin in different tissue compartments
* SHould be possible with other AG

Question 22

What is the only AG that is bacteriostatic?

Answer 22

Spectinomycin

Question 23

What is neomycin used for?

Answer 23

Neomycin B:
* Preoperative bowel sanitation

Doen’t absorb in intact skin