Mechanism of Action of Tetracyclines (Broad-Spectrum 30S Ribosome Inhibitors)

Introduction

Tetracyclines are a class of broad-spectrum bacteriostatic antibiotics that inhibit bacterial protein synthesis. Common examples include tetracycline, doxycycline, minocycline, and demeclocycline. They are effective against a wide variety of Gram-positive, Gram-negative, and atypical organisms, including Rickettsia, Chlamydia, Mycoplasma, and Borrelia.

Due to their broad usage and distinct mechanism, tetracyclines are high-yield topics for USMLE, NCLEX, GPAT, and NEET-PG, especially in infectious disease and microbiology questions.

---

Stepwise Mechanism of Action of Tetracyclines

1. Entry into the bacterial cell
   Tetracyclines enter Gram-negative bacteria via porin channels and actively cross the inner membrane using energy-dependent transport systems.
2. Binding to the 30S ribosomal subunit
   They bind reversibly to the 30S subunit of the bacterial ribosome at the A-site.
3. Blocking aminoacyl-tRNA attachment
   Tetracyclines prevent the binding of aminoacyl-tRNA to the ribosomal acceptor site, halting elongation of the peptide chain.
4. Inhibition of bacterial protein synthesis
   By stopping tRNA binding, they block translation, thereby inhibiting bacterial growth.
5. Selective toxicity
   Mammalian cells lack the tetracycline transport system, so their ribosomes are not affected.

---

Pharmacokinetic Parameters of Tetracyclines (e.g., Doxycycline)

Parameter	Value
Bioavailability	90–100% (doxycycline)
Half-life	12–24 hours
Protein binding	~90%
Metabolism	Minimal hepatic metabolism
Excretion	Fecal (doxycycline), renal (others)
CNS penetration	Moderate

---

Clinical Uses of Tetracyclines

• Rickettsial infections (e.g., Rocky Mountain spotted fever)
• Chlamydia infections (STIs, PID)
• Mycoplasma pneumoniae (atypical pneumonia)
• Lyme disease (Borrelia burgdorferi)
• Brucellosis and plague
• Acne vulgaris (oral doxycycline)
• Malaria prophylaxis
• Helicobacter pylori (in combination therapy)

---

Adverse Effects of Tetracyclines

• Photosensitivity – sunburn-like reaction
• GI irritation – nausea, vomiting, esophagitis
• Tooth discoloration and enamel hypoplasia (in children)
• Hepatotoxicity (rare but serious in pregnancy)
• Fanconi syndrome (expired tetracycline use)
• Superinfections – C. difficile, Candida
• Vertigo (minocycline)

---

Comparative Analysis: Tetracycline vs Doxycycline

Feature	Tetracycline	Doxycycline
Bioavailability	~60–70%	~90–100%
Excretion	Renal	Fecal
Half-life	Shorter	Longer
Use in renal failure	Avoid	Safe
Photosensitivity	Moderate	High

---

Practice MCQs

Q1. Tetracyclines inhibit protein synthesis by binding to:
a. 50S subunit
b. 30S subunit ✅
c. DNA gyrase
d. RNA polymerase

Q2. The primary action of tetracyclines is:
a. Prevent peptide bond formation
b. Block translocation
c. Block tRNA binding ✅
d. Cause mRNA misreading

Q3. Tetracyclines are contraindicated in:
a. Adults with acne
b. Pregnant women ✅
c. Diabetic patients
d. Patients with hypertension

Q4. Which side effect is seen with expired tetracyclines?
a. Nephrotoxicity
b. Fanconi syndrome ✅
c. QT prolongation
d. Photosensitivity

Q5. Which organism is treated with doxycycline?
a. Plasmodium falciparum
b. Mycoplasma pneumoniae ✅
c. MRSA
d. Pseudomonas

Q6. Tooth discoloration in children is due to:
a. Protein synthesis inhibition
b. Iron chelation
c. Calcium binding by tetracycline ✅
d. Enzyme inhibition

Q7. Doxycycline is preferred in renal failure because:
a. It is hepatically cleared
b. It is fecally excreted ✅
c. It is less toxic
d. It inhibits CYP450

Q8. Tetracyclines should not be taken with:
a. Iron
b. Calcium
c. Antacids
d. All of the above ✅

Q9. Minocycline can cause:
a. Ototoxicity
b. Hepatotoxicity
c. Vertigo ✅
d. Hypoglycemia

Q10. Which infection is not treated with tetracyclines?
a. Brucellosis
b. Rickettsia
c. Tuberculosis ✅
d. Lyme disease

---

FAQs

Q1: Are tetracyclines safe in pregnancy?
No, they are contraindicated due to fetal tooth and bone toxicity.

Q2: Why avoid dairy with tetracyclines?
Calcium binds the drug and reduces oral absorption.

Q3: Can doxycycline be used in renal failure?
Yes, because it is fecally excreted, unlike other tetracyclines.

Q4: Do tetracyclines cross the placenta?
Yes, and they can affect fetal bone and teeth development.

Q5: What should patients avoid during therapy?
Avoid sun exposure, iron supplements, and antacids.

---

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/NBK539844/