Core structures of Aminoglycoside (three ex.)
1,3 diaminocyclitol structures
7 Clinically important Aminoglycosides
- Amikacin A
Aminoglycoside MOA (general and specific)
Bind 30S subunit - inhibit protein synthesis
Bind to the 16S rRNA forming the A site = interferes with formation of the initiation complex, blocks translation, and elicits premature termination
Aminoglycosides also cause impairment of ______
proofreading functions of the ribosome
(resulting in nonsense protein)
**nonsense proteins affect cell wall function
What effect do the "nonsense" proteins have on the cell?
They impair the function of the cell wall
(causes membrane destabilization, allowing more Aminoglycoside to enter the cell and completely halt protein synthesis)
Ultimately, Aminoglycosides cause _______ and ______ resulting in cell death
leakage of ions and disruption of the cell membrane
How does the Aminoglycoside get into the cell
Displacement of Mg++ and Ca++ ions that form salt bridges with Phosphate groups (on phospholipids) makes the membrane more permeable.
Passage of Aminoglycosides through the cytoplasmic membrane occurs...
via active transport
How do bacteria inactivate Aminoglycosides?
The genes responsible for enzymatic metabolism of Aminoglycosides can be...
Many of these enzymes...
...transferred to other bacteria
Many enzymes have cross-resistance specificity
Aminoglycosides are not metabolized by...
They are largely excreted unchanged via the urine.
Three mechanisms for Aminoglycoside resistance in bacteria
Metabolism (acylation, adenylation, and phosphorylation)
Altered ribisomes (16S altered by point mutations)
Altered Aminoglycoside uptake (reverts after drug removal)
All Aminoglycosides are ____ and _____
ototoxic (irrev.) and nephrotoxic (rev.)
3 Risk factors for ototoxicity of Aminoglycoside use
- Other ototoxic drugs (loop diuretics, vancomycin)
- Compromised renal function
- Genetic vulnerability
Aminoglycoside + loop diuretics =
potentiated nephortoxicity of both.
Monitor creatinine clearance, discontinue if evidence of ototoxicity appears (dizzy, vertigo, tinnitus)
Less common Aminoglycoside effect
(requires high dose)
Respiratory paralysis can be reversed by ___ or ____
Neostigmine or calcium gluconate
Aminoglycoside toxicity is more likely if Tx involves... (4)
- > than 5 days duration
- renal impairment
- high dose
Spectrum and use of Aminoglycoside
broad spec (+/-)
but mainly used for Gram -
Aminoglycosides are often used in combo with ____
but must be administered in different compartments to avoid rxn!
Penicillin/Aminoglycoside combo used to treat...
Streptomycin used to treat...
Gentamicin is used for....(4)
Joint/bone infections (caused by susceptible Gram-)
Aminoglycoside-resistant bacteria common in...
Amikacin has retained activity against ____.
It's used to treat ____.
Aminoglycoside-resistant strains in hospital.
Most aminoglycosides are based on _______
High risk patients should be assed by ______ during aminoglycoside course