Mechanism of Action of Aminoglycosides

Introduction

Aminoglycosides are potent bactericidal antibiotics used mainly against aerobic Gram-negative bacilli and serious systemic infections. Common examples include gentamicin, amikacin, tobramycin, streptomycin, and neomycin. Unlike most protein synthesis inhibitors, aminoglycosides are bactericidal, not bacteriostatic. They bind to the 30S subunit of the bacterial ribosome and cause misreading of mRNA, leading to faulty protein synthesis and bacterial death.

They are a high-yield topic in USMLE, NCLEX, GPAT, and NEET-PG, particularly due to their unique properties, synergy with β-lactams, and nephrotoxicity.

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Stepwise Mechanism of Action of Aminoglycosides

1. Initial entry via porins in outer membrane
   Penetration of the outer membrane of Gram-negative bacteria occurs through porin channels.
2. Oxygen-dependent active transport across inner membrane
   Transport into the cytoplasm is energy-dependent, requiring aerobic conditions — hence, ineffective in anaerobic environments.
3. Binding to 30S ribosomal subunit
   Aminoglycosides bind irreversibly to the 16S rRNA of the 30S subunit.
4. Interference with initiation complex formation
   This prevents the assembly of the functional ribosome, halting protein synthesis.
5. Misreading of mRNA
   Causes incorrect amino acid incorporation, producing non-functional or toxic proteins.
6. Disruption of bacterial membrane
   Faulty proteins may insert into the cell membrane, increasing membrane permeability, causing leakage and death.

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Pharmacokinetic Parameters of Aminoglycosides (e.g., Gentamicin)

Parameter	Value
Bioavailability	Poor orally; given IV/IM
Half-life	2–3 hours
Protein binding	Low (~10%)
Metabolism	Not metabolized
Excretion	Renal (unchanged)
Volume of distribution	Extracellular fluid compartment

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Clinical Uses of Aminoglycosides

• Severe Gram-negative infections (Pseudomonas, Klebsiella, E. coli)
• Sepsis and bacteremia
• Endocarditis (in combination with penicillin/vancomycin)
• Tuberculosis (streptomycin as second-line)
• Pelvic and abdominal infections (synergistic use)
• Bowel sterilization before surgery (neomycin, oral)
• Plague and tularemia

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Adverse Effects of Aminoglycosides

• Nephrotoxicity (dose-dependent, reversible)
• Ototoxicity (irreversible; affects cochlea and/or vestibule)
• Neuromuscular blockade (rare but life-threatening)
• Teratogenicity (Category D – avoid in pregnancy)
• Allergic reactions (rare)

Monitor renal function and drug levels in prolonged therapy.

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Comparative Analysis: Gentamicin vs Amikacin

Feature	Gentamicin	Amikacin
Spectrum	Gram– (moderate)	Broad (including resistant strains)
Ototoxicity risk	Higher (vestibular)	Lower (more cochlear)
Use in TB	No	Yes (less preferred)
Cost & availability	Cheaper, widely available	Costlier, reserved use
Resistance	Higher due to modifying enzymes	Lower (less susceptible)

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Practice MCQs

Q1. What is the ribosomal target of aminoglycosides?
a. 50S subunit
b. 30S subunit ✅
c. RNA polymerase
d. Topoisomerase

Q2. Aminoglycosides are ineffective in:
a. Aerobic Gram– bacilli
b. Anaerobic infections ✅
c. UTIs
d. Endocarditis (with synergy)

Q3. Which adverse effect is irreversible?
a. Nephrotoxicity
b. Ototoxicity ✅
c. Nausea
d. Rash

Q4. Aminoglycosides inhibit bacterial protein synthesis by:
a. Inhibiting DNA polymerase
b. Disrupting membrane potential
c. Causing mRNA misreading ✅
d. Blocking tRNA binding

Q5. Why are aminoglycosides used with β-lactams?
a. Reduce resistance
b. Improve renal function
c. Synergistic killing ✅
d. Enhance absorption

Q6. Which aminoglycoside is used in TB?
a. Gentamicin
b. Streptomycin ✅
c. Neomycin
d. Tobramycin

Q7. Aminoglycoside excretion route is:
a. Liver
b. Skin
c. Lungs
d. Kidneys ✅

Q8. Which route is preferred for systemic use?
a. Oral
b. IV or IM ✅
c. Rectal
d. Intrathecal

Q9. Which electrolyte imbalance can aminoglycosides cause?
a. Hypernatremia
b. Hypocalcemia
c. Hypomagnesemia ✅
d. Hyperkalemia

Q10. What is the function of 16S rRNA site in aminoglycoside action?
a. Peptide bond formation
b. Ribosome assembly
c. mRNA decoding ✅
d. Translocation

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FAQs

Q1: Are aminoglycosides safe in pregnancy?
No, they are Category D, with risk of fetal ototoxicity.

Q2: Can they be used orally for systemic infections?
No, oral absorption is negligible; only local gut action.

Q3: Do aminoglycosides cross the BBB?
Poorly. Use intrathecal/intraventricular routes in meningitis.

Q4: Why is once-daily dosing used?
It maximizes concentration-dependent killing and reduces toxicity.

Q5: What is the synergistic combination with penicillin used for?
Mainly in enterococcal endocarditis and other Gram+ infections.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK548555/