antifungals

• opportunistic infections by fungi

  • more and more common in hospitals - high mortality rates
  • more common in pts w/ compromised immune systems (AIDS pts, after cancer chemotherapy or organ transplantation)
  • some common pathogens:
  • candida spp (yeast)
  • aspergillus spp (mold)
  • pneumocistis carinii
  • cryptococcus (hidden seeds)
  • mucor (mold)
• biochemical targets for antifungal chemotherapy

  1. disruption of fungal cell membrane

  • suppression of the synthesis of ergosterol (by azoles, allyl amines/naf-fines, etc.)
  • direct binding and permeation (by polyenes, etc.)

  1. inhibition of fungal cell wall synthesis (by echinocandins)
  2. inhibition of fungal DNA synthesis (eg flucytosine)
• agents to treat invasive fungal infections

  1. azoles
  2. polyenes

  • different formulations of amphotericin B

  1. echinocandins

  • capsofungin
  • micafungin
  • anidulafungin

  1. flucytosine
• MOA of antifungal azole compounds

  • forms a bond to the heme iron of CYP450
  • azole compounds
  • containing an imidazole/triazole ring and a nonpolar moiety of aromatic rings
  • mimics ergosterol precursor and inhibits to 14-alpha-demethylase (a CYP)
  • a key enzyme in biosynthesis of ergosterol
  • the fungal equivalent of cholesterol in mammalian cell membranes
  • accumulation of abnormal steroids in the fungal membrane
  • fungal membrane becomes leaky, leading to cell death
• the azole antifungal compounds inhibits CYP450 enzymes

  • azole compounds do not severely interfere the CYP isozyme responsible for the cholesterol synthesis but inhibits other drug metabolizing CYP isozymes
  • potentially causing serious drug-drug interactions if given systemically
• the azole antifungal compounds inhibits CYP450 enzymes (cont.)

  • examples:
  • 1) ketoconazole and itraconazole
  • strong inhibitors of CYP3A4, but very weak inhibitors of CYP2C9 - interaction w/ agent cisapride (cardio side effects), hypnotic triazolam, immunosuppressant cyclosporine
  • 2) fluconazole
  • strong inhibitor of CYP2C9 but weaker inhibitor on CYP3A4 - interaction w/ warfarin, phenytoin
• direct fungal membrane disruptors

  • undecylenic acid
  • nonspecific interaction w/ cell membrane components
  • topically applied
  • nystatin
  • topically applied
  • too toxic to be used systemically
  • amphotericin B
  • can be used systemically as a drug of choice for life-threatening fungal infections but has serious toxicity (renal toxicity, fever, shaking chills, hypotension, etc.)
  • natamycin
  • topically applied for fungal infection of the eye

  
• ambisome

  • formulation of amphotericin B by liposomes based on phospholipids
  • amphotericin B is incorporated in the lipid bilayer of liposomes (lipid vesicles w/ an aqueous interior)
  • the liposomes are 45 - 90 nm in diameter
  • the only true liposome formulation of amphotericin B
• MOA of echinocandins - fungal cell wall synthesis inhibitors

  • caspofungin
  • micafungin
  • anidulafungin
  • target enzyme: beta-(1,3)-D-glucan synthase
  • gene name: Fsk1 and Fsk2
  • basis of selective toxicity: cell wall is critical for the integrity of fungal cell walls but not present in mammalian cells
• structure of fungal cell wall

  1. cellular membrane comprising ergosterol and phospholipids
  2. high molecular weight, cell surface proteins such as invertase and acid phosphatase
  3. polysaccharide layer - essential for withstanding osmotic pressure
  4. strongly associated for external protein layer (fibrillar, essential for cell adhesion)

  
• structural features of echinocanins

  • large molecule (MW ~ 12000
  • amphilic
  • 2 chemical moieties:
  • a cyclic hexapeptide moiety w/ unusual amino acid residues (charged in capsofungin and micafungin)
  • a lipophilic chain, which is thought to interact w/ the lipid bilayers
  • detailed mode is binding w/ the enzyme is unknown
• pharmaceutical properties of echinocandins

  • poor oral bioavailability, given only by slow IV infusion (over ~ 1h)
  • capsofungin and micafungin are freely soluble in water whereas anidulafungin is no
  • after reconstitution from lyophilized powder, capsofungin and micafungin solutoins can be kept for 24 - 48 h whereas anidulafungin needs to be used immediately
  • adverse effect: immune shock (histamine release, brochiolar spasm, etc.) if the infusion is too fast
  • metabolism: slowly taken up by the liver and degraded in the liver by hydrolysis and N-acetylation
  • long terminal half life (11 - 18 h)
• known mechanism of resistance to echinocandins

  • mutations of Fsk1 gene which decrease the drug's binding to the beta-(1,3)-D-glucan synthase