[tinea capitis], nails [tinea unguium; Microsporum canis, Trichophyton mentagrophytes]),
subcutaneous (abscess in muscle or even bone; Sporothrix schenckii) or deep (diffuse,
systemic infection, possibly fatal; Histoplasma capsulatum, Blastomyces brasiliensis).
In recent years, the incidence and severity of human fungal infections have increased
dramatically. The use of powerful immunosuppressive agents for cancer chemotherapy
and for organ transplant, combined with the AIDS epidemic, has led to this significant
increase. However, in healthy individuals, a normally functioning immune system tends
to ward off fungal infections.
Drug design for fungal infections is more challenging than for bacterial infections.
Fungi are “more sophisticated” and their cellular structure starts to more closely
approximate mammalian cellular structure, leading to design challenges in developing
agents that are toxic to fungi but nontoxic to humans. One vulnerable feature of fungal
biochemistry is the structure of the membrane. There is a fundamental difference in
lipid composition between fungal and mammalian cells. Ergosterol is the predominant
membrane sterol lipid in fungi; cholesterol is the principal sterol in human cells. This
is a biochemical difference that can be exploited for drug design. Another significant
difference is that fungi (like bacteria) have cell walls; mammalian cells do not.
Accordingly, possible druggable targets for antifungal drug design include:
- Fungal membrane disruptors, via mechanical insertion
- Ergosterol biosynthesis inhibitors, via 14α-demethylase enzyme inhibition
- Ergosterol biosynthesis inhibitors, via squalene epoxidase enzyme inhibition
- Ergosterol biosynthesis inhibitors, via ∆^14 -reductase enzyme inhibition
- Fungal cell wall disruptors
Of these five targets, those that involve membrane biochemistry (targets 1–4) have
proven to be the most successful.
Streptomyces nodosus produces natural products such as amphotericin A and B.
These are macrocyclic (large-ring) compounds containing numerous (three to seven)
double bonds and multiple hydroxyl groups which are usually located on one side of the
molecule. Amphotericin B (9.103) and the very similar nystatin (9.104) are antifungal
582 MEDICINAL CHEMISTRY