Aminoglycosides (MC) - Block 2 Flashcards
What is the pharmacophore of aminoglycosides?
1-3 diaminoinositol in sugars
What are the properties of AG?
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
MOA of aminoglycosides?
- Bind to the 16S rRNA portion of 30S ribosomal subparticles
- Imparis proofreading of the ribosome
- 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
How do AG disrupt bacterial membrane?
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
How do AG enter the cell if they are polar?
- Bind to external lipopolysacc and diffuse into the cells in small amounts
- UPtake is inhibited by Ca2+ and Mg2+ ions
- Ions are partially incompatible therapeutically
What is the purpose of AG binding to 16S site?
- Shuts down protein synthesis
- Formation of nonsense protein
- Formation of incomplete protein
Activity of AG?
Bacteriocidal for G- (diffuses through porins passiely):
* Actively transported across cytoplasmic membrane
Not good for G+
AG resistnce?
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
What are the covalent modifications that result in resistance?
- Phsophorylation
- Acetylation
- Nucleotidylation (Adenylation)
Hypothesis of resistance mechanisms?
AMEs bind AG with a similar conformation (1,3-diamine)
How does amikacin bypass resistance?
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
What is the purpose for HABA functional group?
Provides incognition to the rest of the drug
AG spectrum of activity?
ESKAPE and SPACE pathogens
ADR of AG?
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
What is the source of instability of streptomycin?
a-hydroxylaldehyde
What is the source of kanamycin instability?
Gets O-phosphorylated enzymes APH(3’)-I and APH(3’)-II
Describe the structure amikacin?
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
Strcture of tobarmycin?
- Lacks C3’ hydroxyl group
- Not a substrate for APH(3’) or APH(3’)-II
Gent resistant P. aeruginosa
Enzymes of AG metabolism?
- Acetylation (aminoacetyle tranferases)
- Phosphorylation (phospho transferase)
- Adenylation (nucleotidyl transferase)
Structure of gentamycin?
- :acks functional groups that serve as targets for R facotr enzymes
- Inactivated through c-2’ adenylation and acetylation C6’, C1 and C2’
What ABX is incompatible with beta lactams? Why?
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
What is the only AG that is bacteriostatic?
Spectinomycin
What is neomycin used for?
Neomycin B:
* Preoperative bowel sanitation
Doen’t absorb in intact skin
