trans

420 DRUG RESISTANCE
FIGURE 16.7 Drug transport and targets in Trypanosoma brucei. Melarsoprol is taken up by the P2 adenosine
transporter. Mutations in P2 lead to reduced adenosine uptake and reduced melarsoprol uptake. The diamidines
pentamidine and berenil are also taken up by P2, and mutations in P2 lead to reduced accumulation of pentamidine,
although pentamidine is also taken up by high affinity (HAPT1) and low affinity (LAPT1) pentamidine transporters.
Eflornithine inhibits the enzyme ornithine decarboxylase (ODC). In eflornithine-resistant mutants the rate of
ornithine uptake was augmented. Suramin is proposed to enter the cell bound to low density lipoprotein (LDL),
through receptor-mediated endocytosis. The veterinary drug isometamidium is accumulated into the mitochondria,
and resistance to this class of drug has been associated with changes in the mitochondrial electrical potential ().
to melarsoprol refractoriness, but is not the
only gene product involved. Other markers of
resistance may correspond to ABC proteins.
Indeed, several ABC transporters have been
described in T. brucei, and one gene highly
similar to the Leishmania PGPA was recently
cloned and transfected in T. brucei and was
shown to confer melarsoprol resistance. The
mechanism by which it confers resistance
(efflux, drug sequestration) is unknown, but
it will be highly interesting to test whether
mutations in this gene are correlated to melarsoprol
resistance in clinical isolates. The availability
of drug resistance markers could be used
in diagnostic tests for evaluating resistance in
the field.
Eflornithine
Eflornithine, or D, L--difluoromethylornithine
(DFMO) is used against MelB refractory latestage
T. b. gambiense infections. Its price and
its availability limit its use in countries where
infection is endemic. The drug, first developed
as an anti-cancer agent, is a suicide inhibitor of
the cellular enzyme ornithine decarboxylase
(ODC), the limiting step in polyamine biosynthesis.
Polyamines are essential for eukaryotic
cell division and play a role in differentiation.
Polyamines are also a component of trypanothione
(Figure 16.6). Although DFMO is active
against both the parasite and the host ODCs,
its selective toxicity is the result of the longer
MEDICAL APPLICATIONS