voriconazole, the compound appeared on the market
in 2002, and the other two compounds, ravuconazole
and posaconazole, are in the final stages of clinical
trials. Thus, compared with the situation only a decade
ago, when ketoconazole was the drug of choice, there
is now a wide range of azoles available for the treat-
ment of specific mycoses.
For all these azole drugs, the consequence of block-
ing the demethylation step of the ergosterol biosynthetic
pathway is to deplete the concentration of ergosterol
so that fungi incorporate other sterols in the membrane.
The effect of this can be studied in a model system,
by exploiting the fact that Saccharomyces cerevisiaecan
grow both anaerobically and aerobically. When grown
aerobically, Saccharomycessynthesizes ergosterol; but
when grown anaerobically Saccharomycesneeds to be
supplied with sterols, because these are products of aer-
obic biosynthetic pathways (Chapter 7). If anaerobic cells
of Saccharomycesare supplied with a different sterol such
as lanosterol, they become leaky and cannot assemble
the wall in the normal way. In this respect it will be
recalled that the major wall-synthetic enzymes, chitin
synthase and glucan synthase, are integral membrane
proteins (Chapter 4), so presumably any change in the
membrane composition could affect these enzyme
functions. In Candida, one of the effects of the azole
drugs is to prevent the phase transition from yeasts to
hyphae. As we noted in Chapter 16, this phase transi-
tion is important for invasion of tissues and for allow-
ing Candidato break out of phagocytes.5-Flucytosine (5-FC)5-FC is a fluorine-substituted nucleoside, developed
originally as an antitumour agent but it has an addi-
tional role as an antimycotic agent for the treatment of
systemicCandida andCryptococcus. Its mode of action
is shown in Fig. 17.15. It is taken into a fungal cell by
the cytosine permeaseof the cell membrane, then
deaminated to 5-fluorouracilwhich, through a series
of steps, is incorporated into RNA in place of uracil,
causing impaired RNA function. It also impairs DNA
synthesis because one of the products of 5-fluorouracil
inhibits the enzyme thymidylate synthase in the
pathway that generates thymidine nucleotides.PRINCIPLES AND PRACTICE OF CONTROLLING FUNGAL GROWTH 353
Fig. 17.15Mode of action of the synthetic pyrimidine 5-flucytosine.