trans

416 DRUG RESISTANCE
FIGURE 16.6 Trypanothione metabolism and antimony resistance in Leishmania. Trypanothione (TSH) is made
of two molecules of glutathione (GSH) conjugated to the polyamine spermidine. The pentavalent antimony (SbV)
used for treating Leishmania is reduced to the trivalent form (SbIII). The level of TSH is increased in Leishmania
cells resistant to metals. TSH is conjugated to SbIII, possibly by a hypothetical conjugase. The metal–thiol conjugate
can be extruded from the cell by a plasma membrane efflux pump or sequestered inside a vacuole by the ABC
transporter PGPA. -GCS: -glutamylcysteine synthetase; GS, glutathione synthase; ODC, ornithine decarboxylase;
SPDS, spermidine synthase; GSS, glutathionespermidine synthase; TRS, trypanothione synthase; AdoMetS,
S-adenosylmethionine synthase; AdoMetDC, S-adenosylmethionine decarboxylase.
transport suggesting that it possibly enters into
Leishmania through the parasite polyamine
transport system. Resistance to pentamidine
has been induced in vitro in several Leishmania
species, both as promastigotes and as amastigotes.
Resistance can be maintained stably
throughout the life cycle of the parasite, and
is associated with changes in the intracellular
concentration of arginine, ornithine and
putrescine. This may be due to alterations in
polyamine carriers, but perhaps also to modulation
of the activity of key enzymes in the
polyamine biosynthesis pathway, such as
ornithine decarboxylase and spermidine synthase
(Figure 16.6). Analysis of pentamidineresistant
mutants indicated additional defects
in the uptake and efflux of several substrates,
which may be due to a perturbation of lipid
MEDICAL APPLICATIONS