Abstract: Hydroperoxide metabolism in diverse pathogens is reviewed under
consideration of involved enzymes as potential drug targets. The common
denominator of the peroxidase systems of Trypanosoma, Leishmania, Plasmodium,
and Mycobacterium species is the use of NAD(P)H to reduce hydroperoxides
including peroxynitrite via a flavin-containing disulfide reductase, a
thioredoxin (Trx)-related protein and a peroxidase that operates with thiol
catalysis. In Plasmodium falciparum, thioredoxin- and glutathione dependent
systems appear to be linked via glutaredoxin and plasmoredoxin to terminal
thioredoxin peroxidases belonging to both, the peroxiredoxin (Prx) and
glutathione peroxidase (GPx) family. In Mycobacterium tuberculosis, a
catalase-type peroxidase is complemented by the typical 2-C-Prx AhpC that, in
contrast to most bacteria, is reduced by TrxC, and an atypical 2-C-Prx reduced
by TrxB or C. A most complex variation of the scheme is found in
trypanosomatids, where the unique redox metabolite trypanothione reduces the
thioredoxin-related tryparedoxin, which fuels Prx- and GPx-type peroxidases as
well as ribonucleotide reductase. In Trypanosoma brucei and Leishmania donovani
the system has been shown to be essential for viability and virulence by
inversed genetics. It is concluded that optimum efficacy can be expected from
inhibitors of the most upstream components of the redox cascades. For
trypanosomatids attractive validated drug targets are trypanothione reductase
and trypanothione synthetase; for mycobacteria thioredoxin reductase appears
most appealing, while in Plasmodium simultaneous inhibition of both the
thioredoxin and the glutathione pathway appears advisable to avoid mutual
substitution in co-substrate supply to the peroxidases. Financial and
organisational needs to translate the scientific progress into applicable drugs
are discussed under consideration of the socio-economic impact of the addressed
diseases.
