Antifungals

• Antifungals


  Drugs used to treat fungal infections
• There are around 100,000 species of fungi, 300 of which are presently known to be pathogenic to man
• Types of fungi


  • Mushrooms
  • Yeasts
  • Moulds
• Fungi


  • Able to grow at low water activity
  • Eukaryotes
  • Don't contain chlorophyll, so don't perform photosynthesis
  • Filamentous structures, being made of filaments
  • Produce spores, which is how they reproduce
  • Grow as saprophytes as they don't get perform photosynthesis for energy, instead breaking down and recycling dead plant and animal material, which acts as their energy and nutrient source

  
• Yeast


  Unicellular organisms, reproducing by budding
• Moulds


  • Multicellular filamentous organisms, aka hypha and mycelium
  • Reproduce by spores
• Dimorphic fungi


  Fungi that occur in both yeast and mycelial (mould) forms
• Mycosis


  A disease caused by a fungus
• Mycotic diseases are generally not communicable, however, some can transmit between people
• Types of Fungal Diseases


  • Allergies
  • Mycotoxicosis
  • Mycoses
• Systemic infection (deep)


  Affecting tissues or organs, e.g. histoplasmosis which is a disease that affects primarily the lungs
• Superficial infection


  Affecting skin, nails, scalp, toes, mucous membranes etc: dermatomycoses (skin, hair, nails), candidiasis (mucous membranes of mouth (thrush), vagina (yeast) or skin)
• Fungal Cell Wall


  • Maintain structure
  • Protect against mechanical injury
  • Prevent osmotic lysis
  • Provide passive protection against internalisation of potentially harmful macromolecules
  • Determine final morphology of fungus
  • Composed largely of chitin, a polymer of N-acetylglucosamine

  
• Due to the different characteristics of fungi and bacteria, any antibiotic that works on the cell wall of the bacteria won't work on fungi
• Moulds


  • Multicellular organisms
  • Reproduce asexually by spore formation or by fragmentation
  • Grow on a wide variety of substrates
  • Used in production of antibiotics and cheeses
  • Aerobic organisms — require oxygen to respire/grow
  • Can be killed by mild heat treatments (but mould spores are more resistant to heat, so when conditions are favourable, the spores will grow and develop into fungi)
• Typical Yeast Cell


  • Unicellular and made of a cell wall which contains nucleus, mitochondrion and storage granules
  • Often forms a bud: yeast cell will elongate and have small yeast generated from that site. Once budding has occurred, a bud scar remains on the cell wall
  • Parent cell and bud contain vacuoles
  • Yeasts have 3 membranes: cell membrane, vacuolar membrane and nuclear membrane
• Fungal Reproduction


  • Growth and spread of hyphal filaments
  • Asexual production of spores
  • Simple division — 'budding'
  • Some produce spores as a result of sexual reproduction
• Examples of Fungal Diseases


  • Pityriasis versicolour
  • Tinea pedis (athlete's foot)
  • Onychomycosis (nail infection)
  • Chromoblastomycosis
  • Blastomycosis
  • Candidosis/candidiasis
• Targets for Antifungal Therapy


  • Echinocandins
  • Azoles
  • 5Fluroctyosine
  • Polyenes
  • Griseofulvin
• Inhibition of Cell Wall Synthesis


  Cyclic lipopeptide act by interfering with fungal cell wall synthesis by inhibition of ß-(1,3 D-glucan synthase. Without this enzyme, ß-(1,3 D-glucan can't be produced, so cell wall will be flaccid and cell will die.

  
• Inhibition of Cell Membrane Synthesis


  1. Polyene Macrolide Antibiotics bind to membrane ergosterol in the fungal cell, altering membrane integrity with leakage of ions and macromolecules causing irreversible fungal cell damage

  2. Azoles antifungals block synthesis of ergosterol from lanosterol, inhibiting fungal membrane growth and interfering with membrane-bound enzyme systems, so cell becomes damaged
• Inhibition of Nucleic Acid Synthesis


  In fungal cells, 5Flucytosine is converted into 5-fluorouracil, which inhibits both DNA and RNA synthesis
• Inhibit Fungal Mitosis


  Binds to intracellular microtubular protein and inhibits fungal mitosis
• Non-specific Treatments for Dermatophyte infections


  • Whitfield's Ointment
  • Castellani's Paint
  • Undecenoate fatty acid
  • Ciclopirox
  • Tolnaftate
• Non-specific Treatments for Pityriasis versicolor


  • Selenium Sulphide 2.5%
  • Sodium thiosulphate 20%