trans

428 DRUG RESISTANCE
pharynx, the body wall and the uterine muscles
of nematodes, leading to starvation and paralysis.
The evidence suggests that several gene
products are involved in the mechanism of
action of ivermectin. Intensive usage of ivermectin
has selected for resistant parasites in
the field, but fortunately for human beings,
resistance has so far only been detected in
nematodes of goats and sheep. Ivermectinresistant
strains are sometimes cross-resistant
to structurally unrelated drugs, and multidrugresistance
reversing agents can partially reverse
ivermectin resistance in Haemonchus contortus.
Genetic analyses have linked a number
of P-glycoprotein homologs to ivermectin
resistance in a number of worm genera. This
makes sense since ivermectin is an excellent
substrate of the mouse MDR1a P-glycoprotein.
In the nematode Caenorhabditis elegans simultaneous
mutations in three genes encoding
glutamate-gated chloride channel -type subunits
confers high-level resistance to ivermectin.
A number of similar channels have
been found in pathogenic worms, and polymorphisms
in one glutamate-gated chloride
channel was linked to resistance in H. contortus.
Both target mutations and transport alteration
can therefore lead to ivermectin resistance in
worms, and other studies suggest that increased
glutamate uptake can also be linked to ivermectin
resistance. It is possible that different
worm species will have different mechanisms
of resistance towards ivermectin, and at present
resistance has not been reported in O. volvulus,
the etiological agent of onchocerciasis.
Resistance to levamisole and pyrantel
Levamisole and pyrantel are nicotinic
anthelmintics that act as cholinergic agonists in
nematodes, most likely by inhibiting the nicotinic
acetylcholine receptors of the worms. This
results in depolarization of nematode muscle
cell membranes. In C. elegans a number of
mutations in some of the subunits (lev 1, unc-
29 and unc-38) of the nicotinic acetylcholine
receptor have been correlated with levamisole
resistance, although this remains to be shown
for pathogenic worms. Resistance appears to be
multigenic, although a reduction in the number
or affinity of receptors has nonetheless
been proposed as one possible mechanism for
resistance. Pyrantel also acts on the nicotinic
acetylcholine receptors, and patch-clamp
experiments suggested that pyrantel resistance,
like levamisole resistance, is associated with a
modification of the target.
Resistance to benzimidazoles
Benzimidazoles, the most widely used
anthelmintics, are used mainly in the treatment
of veterinary intestinal nematode infections.
They selectively inhibit tubulin polymerization,
possibly by binding specifically to the
parasite -tubulin. Resistance to benzimidazole
is now a problem, particularly in the ruminant
parasite H. contortus and in small strongyles of
horses. Point mutations in the -tubulin gene,
particularly at position 200, are associated
with resistance to this class of drug. The role of
these mutations in resistance was confirmed
by gene transfection in C. elegans and by biochemical
means. Other alterations in the tubulin
genes can occur in highly resistant worms.
The understanding of the main resistance
mechanism has led to several PCR-based diagnostic
tests for the detection of resistance
to benzimidazole in a number of species of
gastrointestinal worms.
CLINICAL IMPLICATIONS
AND OUTLOOK
Drug resistance complicates the treatment of
parasite infections. Studies on drug resistance
MEDICAL APPLICATIONS