18.2 Antifungal agents that target the wall

As we have remarked before, synthesis and assembly of the fungal cell wall is an attractive and highly selective target for therapeutic antifungal drugs because chitin and β-glucans are not found in mammalian cells. Refer to the following sections (CLICK the hyperlinked section titles to view now):

The best-known chitin synthesis inhibitors are naturally occurring antibiotics which are analogues of the chitin synthase substrate, UDP-N-acetylglucosamine. They are called nikkomycin (from the bacterium Streptomyces tendae) and polyoxin (produced by Streptomyces cacaoi var. asoensis) (Fig. 8).

Polyoxin is an informal name, although widely used in the literature, it is only approved by the Japanese Ministry of Agriculture, Forestry and Fisheries; whereas the name polyoxorim has been assigned by ISO (the International Organisation for Standardisation, http://www.iso.org/).

Comparison of the structures of the fungicides nikkomycin and polyoxorim
Fig. 8. Comparison of the structures of the fungicides nikkomycin and polyoxorim (polyoxin) with (centre) the structure of UDP-N-acetylglucosamine which is the normal substrate of chitin synthase. The generic structure of polyoxorim is shown; in polyoxin B, R = CH2OH; in polyoxin D, R = COOH; and in polyoxin J, R = CH3.

Nikkomycins and polyoxorims function as potent and specific competitive inhibitors of chitin synthase, competing as analogues of its normal substrate UDP-N-acetylglucosamine (also shown in Fig. 8). Zinc salts of 'polyoxin D' (the most potent of the 13 different polyoxorims which are designated A to M) are used in Japan against rice sheath blight (Rhizoctonia solani; synonym = Pellicularia sasakii) and in the US as a fungicide for turf on golf courses, parks, and amenity lawns. 'Polyoxin B' is effective in controlling powdery mildews on fruit trees and grapevines. Both polyoxin B and D are commercially produced by fermentation with Streptomyces.

Use of these agents as agrochemical fungicides has been hampered by the rapid emergence of resistant fungal strains. Also disappointing is that clinical treatments with nikkomycins and polyoxorims have not proved effective in controlling human mycoses due to limited uptake of the inhibitors into the cytoplasm of the fungal pathogen and their toxicity to animals (in which they act as analogues of other UDP-linked metabolites). With care, they can be used in conjunction with other antifungal agents in clinical treatment strategies; however, antifungal agents that specifically target the chitin component of the fungal cell wall have found limited therapeutic use.

The newest family of naturally occurring antibiotics to be developed to treat life threatening fungal infections are the echinocandins, which includes caspofungin, micafungin and anidulafungin (Boucher et al., 2004). These are lipopeptides that feature a cyclic (hexa-) peptide linked to a long chain fatty acid (Fig. 9).

They inhibit β-(1,3) glucan synthase and consequently disrupt cell wall formation and prevent fungal growth. This is a non-competitive inhibition and although the exact mechanism is not understood yet, echinocandins are known to bind to the glucan synthase catalytic subunit.

The echinocandin antifungal agent known as caspofungin acetate
Fig. 9. The echinocandin antifungal agent known as caspofungin acetate which is being developed under the brand name Cancidas worldwide, this being a registered trademark of Merck & Co., Inc. (http://www.cancidas.com/cancidas/shared/documents/english/pi.pdf). Cancidas is prepared for intravenous administration.

Echinocandins were discovered during screening of natural products of fungal fermentation for activity specifically against Candida species. The first, called papulacandins, were isolated from a strain of Papularia (= Arthrinium) sphaerosperma, a marine species belonging to the Sordariales (Ascomycota), and lead to the discovery of this entirely new group of broad range antifungals (Traxler, Gruner & Auden, 1977; Boucher et al., 2004).

Treatment of fungi with echinocandins results in swelling and lysis at areas of active cell wall synthesis and the echinocandins have emerged as a promising therapy for aspergillosis and candidiasis (Bowman & Free, 2006) because of their:

  • favourable safety profiles,
  • broad spectrum of activity,
  • high potency,
  • suitability for oral administration (although caspofungin acetate (Fig. 9) is administered intravenously) (Boucher et al., 2004).

Updated December 17, 2016

December 17, 2016