trans

412 DRUG RESISTANCE
whether these represent true resistance
and there is no information on potential
mechanisms.
Resistance in other Apicomplexa
Resistance in Toxoplasma gondii
In addition to malaria, several Apicomplexa
protozoan parasites are important pathogens
of humans and animals. Toxoplasma gondii
is widely distributed with a very high prevalence
in many regions, and can cause serious
infections in immunocompromised patients
(particularly AIDS patients) and in the developing
fetus. Treatment of T. gondii relies on
the combination pyrimethamine–sulfonamide,
with clindamycin and atovaquone as secondline
drugs. Clinical resistance to these antimicrobial
agents has not yet been described, and
since there is no human-to-human transmission,
the likelihood of resistant parasites emerging
is low, although long-term therapy may
select resistant organisms in infected individuals.
Nonetheless, considerable work has been
done on mechanisms of resistance induced
in vitro. Single point mutations in the T. gondii
dhfr-ts can produce pyrimethamine resistance
in T. gondii. Atovaquone targets the cytochrome
bc 1 complex of parasites, which functions
as an acceptor of electrons. T. gondii mutants
selected for atovaquone resistance had mutations
in their cytochrome b gene in regions
corresponding to regions likely to bind the
drug, and in the same residues as found in
atovaquone-resistant Plasmodium. Clindamycin
is a macrolide inhibiting translation
in bacteria. In Toxoplasma, prokaryotic-like
translation takes place in the apicoplast,
a plastid organelle similar to those found
in plants and algae. One possible mechanism
of resistance would be a mutation in the
apicoplast rRNA.
Resistance in Eimeria
Eimeria is a genus closely related to
Toxoplasma that causes coccidiosis, an intestinal
tract disease of domestic fowl that infects
several billion chickens reared annually. A
large number of anticoccidials were developed
in the 1960s and 1970s. The drugs mostly
used are ionophores of the polyether type (e.g.
monensin, maduramicin, salinomycin) that
interfere with membrane integrity. Other
drugs target the folic acid biosynthetic pathway,
the purine biosynthesis or uptake pathways,
or mitochondrial function, and for a
number of effective drugs the mode of action
is not understood. The usefulness of anticoccidial
drugs is jeopardized by the development
of resistance, and several of the strains in
which resistance has been studied were multiply
resistant, suggesting that in some of these
cases broad-range substrate efflux systems
such as P-glycoprotein could be involved in
resistance. The biochemical or molecular
basis of resistance for drug-resistant mutants
either isolated in vitro or from field isolates
has not yet been determined.
Resistance in Cryptosporidium
The protozoan parasite Cryptosporidium
parvum can cause severe diarrhea in immunocompromised
patients. Although many antimicrobial
agents have been tested against this
apicomplexan parasite none has been shown
to be effective. The only drug with some limited
activity is the aminoglycoside paromomycin,
an inhibitor of the translational machinery. It
thus appears that this parasite is intrinsically
resistant to several different anti-protozoal
agents. This has led to the suggestion that an
ABC transporter efflux pump could contribute
to intrinsic resistance, although concrete evidence
for this is lacking. Other mechanisms
MEDICAL APPLICATIONS