New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 374

lacks an apicoplast and is regarded as a distantly related lineage that is, in
fact, not coccidian, but occupies many of the same ecological niches as
the other apicomplexans ( Barta and Thompson, 2006 ). The large subunit of
prokaryote ribosomes is also targeted by various antibiotics. One of these is
the macrolide spiromycin, which is used in chemotherapy against T. gondii
( Greif et al., 2001 ), another is the lincosamide clindamycin effective against
T. gondii most likely due to interference with protein biosynthesis of the
apicoplast ( Fichera and Roos, 1997 ).
3.2. Cytoskeletal Proteins as Drug Targets
Integrity of the cytoskeleton is essential for maintenance and infectiv-
ity of protozoan and helminth parasites. Therefore, its components, espe-
cially tubulin, may constitute suitable targets for antiprotozoal drugs
( Werbovetz, 2002 ). Probably, the most seriously investigated drug acting
against parasite cytoskeletal components is albendazole. Molecular genetic
analysis of resistant vs susceptible organisms has revealed that sensitivity to
albendazole (or other benzimidazoles) in evolutionary distant organisms
such as fungi, nematodes ( Driscoll et al., 1989 ; Kwa et al., 1995 ), platy-
helminthes ( Hemphill and Müller, 2009 ), and various protozoa including
G. lamblia ( Katiyar et al., 1994 ; Kirk-Mason et al., 1988 ) correlates with
the presence of specific alleles of β-tubulin genes. The substitution of
Phe to Tyr in position 200 is sufficient for switching from benzimidazole
sensitivity to resistance as shown using Caenorhabditis elegans as a model
system ( Driscoll et al., 1989 ; Kwa et al., 1995 ). Molecular modeling of
the putative albendazole-binding site in albendazole-resistant Acantham-
oeba β-tubulin indicates that four of 13 residues are different from tubu-
lins of sensitive organisms. Resistance is conferred when, besides Phe200,
Phe167 is replaced ( Henriquez et al., 2008 ). The mode of action of the
benzimidazole triclabendazole, one of the most important flukicides, is
not fully understood but most likely related to the one described for
albendazole ( Brennan et al., 2007 ).
Albendazole and related benzimidazoles interact with recombinant
β-tubulin monomers of sensitive protozoa including G. lamblia and C. par-
vum and inhibit tubulin polymerization. When added to assembled microtu-
bules, depolymerization is, however, not induced ( MacDonald et al., 2004 ).
These molecular data suggest that albendazole has a low toxicity for mam-
malian host cells since they have “resistant” β-tubulin alleles. It is, however,
well documented that albendazole affects growth of embryonic rodent cells
( Whittaker and Faustman, 1991 ) and may therefore be teratogenic.