5-FC is selectively toxic to fungi because mammalian
cells have a low rate of uptake of the molecule and
have little or no ability to convert it to 5-fluorouracil
because they lack the enzyme cytosine deaminase (Fig.
17.15). However, 5-FC affects only a small number of
fungi, notably Candida, Cryptococcus, and Aspergillus
fumigatus, and even these fungi easily developresistance
to it in clinical practice. The cause of this resistance
can be studied in vitroby supplying cells with the vari-
ous intermediates along the pathway shown in Fig.
17.15. Most resistant strains from clinical specimens are
found to be deficient in uridylate pyrophosphorylase
activity, but a few lack a cytosine permease or deami-
nase. Because of the rapid development of resistance,
5-FC is not used alone but in conjunction with other
drugs, especially amphotericin B, with which it has a
significant synergistic effect.
Echinocandins
Echinocandins are naturally occurring secondary
metabolites of fungi, which are now in an advanced
stage of development as novel antifungal agents because
they inhibit the synthesis of β1-3 glucan, one of the
major wall polymers of fungi. Caspofungin(Fig. 17.16),
a polypeptide antifungal, was licensed for clinical use
in 2002. It is active against some Candidaspp. and
Aspergillus fumigatus. Two other compounds of the
same structural class, anidulafunginand mycafungin,
are expected to be licensed soon.
Control of Pneumocystis jiroviciWe noted in Chapter 16 that P. jiroviciis an unusual
fungus which for many years was classified as a pro-
tozoan. The principal means of controlling it is
with the drug pentamidinewhich is thought to act
on DNA. It is also sensitive to the antibacterial agents
trimethoprimand sulfomethoxazole, which disrupt
the folate pathway involved in transfer of groups from
the amino acid serine to a range of other compounds.
P. jiroviciis not affected by the antifungal polyenes or
azoles because it has cholesterol, not ergosterol, in
its cell membrane. However, all three of the echino-
candins mentioned above are active against P. jirovici.The future...Despite the impressive advances that have been made
in controlling fungal infections of humans, and the
recent introduction of the echinocandins, there is still
concern that the pace of development of drugs with
novel modes of action is slow. To quote Odds et al.
(2003), “... the spectre of emergence of resistance is a
real one... and new inhibitors will continue to be re-
quired for effective antifungal therapy in the future.”
In parallel with the development of new antifungal
agents, there is increasing interest in the development
of vaccines to protect against some of the endemic
human-pathogenic fungi. These studies are at a rel-354 CHAPTER 17
H 2 N
O
HO
O
O
O
O
O
HO
HO
OH
OH
HN
NH
HN
H 2 N
OH
OH
NH
H
N
N
N
NH
O
Fig. 17.16Caspofungin, one of the new echinocandin antifungal agents.