Introduction to Fungi, Third Edition

280 HEMIASCOMYCETES
The azole-type fungicides inhibit the enzyme
lanosterol demethylase which is involved in
ergosterol biosynthesis (see Fig. 13.16). A muchused
example is fluconazole (Fig. 10.9b) which is
free from severe side effects. There are several
resistance mechanisms in C. albicans. The most
common, found in 85% of all resistant isolates
(Perea et al., 2001), is based on active exclusion of
the drug by means of ABC (ATP binding cassette)
transporters or similar mechanisms. These are
plasma membrane proteins with numerous
(usually 12) transmembrane domains and two
cytoplasmic ATP-binding domains. Alternating
binding and hydrolysis of ATP changes the conformation
of these proteins, enabling them to
open and close membrane pores. ABC transporters
are often capable of transporting a group
of different metabolites, thereby producing
cross-resistance. The natural role of ABC transporters
probably lies in the exclusion of endogenous
antibiotics, toxins or other substances, e.g.
mating factors in S. cerevisiae. The second most
important type of resistance against azole-type
drugs (65% of all isolates) is a mutation of the
cellular target, i.e. the azole binding site on the
enzyme lanosterol demethylase. The fact that
the occurrences of these two types of resistance
add up to more than 100% indicates that many
clinical C. albicans isolates (about 75%) possess
both resistance mechanisms. A third resistance
mechanism against azoles is the overexpression
of the gene ERG11 encoding lanosterol demethylase,
which occurs in about 35% of resistant
isolates (Perea et al., 2001).
A third group of compounds, the allylamines
(e.g. terbinafine; Fig. 10.9c) act against a different
enzyme involved in ergosterol biosynthesis, squalene
epoxidase (see Fig. 13.16). Terbinafine is
not used extensively on its own, but it is useful
in combination with other drugs in order to
treat infections by resistant Candida strains.
Another target, nucleic acid biosynthesis,
is attacked by 5-fluorocytosine (Fig. 10.9d).
Following uptake, it is deaminated to 5-fluorouracil
and converted to 5-fluoro-UTP or a corresponding
deoxynucleotide, which inhibit RNA
and DNA biosynthesis, respectively. Resistance is
associated with a reduced capacity of the fungus
to metabolize 5-fluorocytosine. Mammalian cells
do not efficiently metabolize this drug but intestinal
bacteria can, which precludes the oral use
of this antibiotic.
A recently described group are the echinocandins
which inhibit b-(1,3)-glucan synthesis.
There is preliminary evidence that echinocandins
such as caspofungin (Fig. 10.9e) do not
act directly on b-(1,3)-synthase but in an indirect
manner by interfering with upstream regulatory
proteins (Edlind & Katiyar, 2004). No drugs
against mannoproteins or aspartic proteases are
as yet commercially available, although treatment
against HIV uses protease inhibitors which
also affect C. albicans (Dupont et al., 2000).
Research efforts into new anti-Candida drugs are
intensive, given that the incidence of Candida
infections is strongly on the increase, few substances
are currently available, and resistance of
Candida against them is becoming a problem.
10.3.4 Ecology and drug resistance of
Candida albicans
Numerous investigations of the distribution of
Candida spp. on their hosts have been carried out.
Generally, C. albicans is by far the most frequent
species, followed by C. parapsilosis. Other species
such as C. glabrata, C. krusei and C. tropicalis
are very much less frequent. Within the species
C. albicans, many different strains exist, and their
colonization pattern has been followed on the
same human host over time (Xu et al., 1999;
Kam & Xu, 2002). Each human being can be
colonized by a diversity of strains. Displacement
of one strain by another is possible, as is the
transfer of strains between humans. Appropriate
analyses of allelic distributions have shown that
the mode of genetic inheritance is predominantly
clonal, i.e. sexual reproduction and
the exchange of genetic material between different
Candida strains do not seem to play an
important role (Lott et al., 1999). There are no
significant differences in the Candida populations
between healthy individuals and AIDS
patients unless, of course, the population
dynamics are shaken up by anti-Candida drug
treatments. In the course of a prolonged treatment
of patients against oral candidiasis,
Martinez et al. (2002) reported the displacement