Lecture Notes: Polyene Antibiotics

Introduction

• Polyene antibiotics are isolated from Streptomyces species.
• They contain conjugated double bonds in a macrocyclic lactone ring.
  • Conjugated double bonds: Alternating double bonds.
  • Macrocyclic lactone ring: A large cyclic ring structure.

Comparison with Macrolides

• Macrolides are antibacterial agents.
• Polyene antibiotics are antifungal agents.
• Polyenes are larger and contain a conjugated system of double bonds.

Types of Polyene Antibiotics

• Based on macrocyclic ring size:
  • 26-membered ring: Example - Natamycin (Pimaricin)
  • 38-membered ring: Examples - Amphotericin B and Nystatin
• Structure includes:
  • Series of hydroxyl groups
  • Glycosidically linked deoxyaminohexose sugar called mycosamine

Examples of Polyenes

• Natamycin: Pentayin with 5 double bonds.
• Nystatin: Hexayin with 6 double bonds.
• Amphotericin B: Heptayin with 7 double bonds.

Activity

• No activity against bacteria, rickettsia, or viruses.
• Highly potent broad-spectrum antifungal agents:
  • Active against protozoa like Leishmania species
  • Effective against pathogenic yeast, molds, and dermatophytes
• Inhibit species like Candida, Cryptococcus, Aspergillus, Cephalosporium at low concentrations.

Limitations

• Limited use for systemic infections due to:
  1. Toxicity
  2. Low water solubility
  3. Poor chemical stability
• Amphotericin B is useful for serious systemic infections but must be solubilized with a detergent.
• Other polyenes are used as topical agents for superficial fungal infections.

Mechanism of Action

• Polyenes have a three-dimensional, barrel-like non-polar structure with a polar sugar cap.
• They penetrate the fungal cell membrane and act as a false membrane component.
• Binding: Bind with membrane sterol, ergosterol, in the fungal cell membrane.
• Effects:
  • Produce an aggregate forming a transmembrane channel.
  • Intramolecular hydrogen bonding (among hydroxyl, carboxyl, amino groups) stabilizes the channel.
  • Alters cell membrane permeability causing cytoplasmic content leakage (especially potassium).
  • Results in cell rupture and death.

Conclusion

• Discussion centered on the structure, types, activity, limitations, and mechanism of polyene antibiotics.
• Next class will focus on specific drugs within polyene antibiotics.