Trypanosoma brucei is the causing agent of
African trypanosomiasis. These parasites possess a unique
thiol redox system required for
DNA synthesis and defense against oxidative stress. It includes
trypanothione and
trypanothione reductase (TryR) instead of the
thioredoxin and
glutaredoxin systems of mammalian hosts. Here, we show that the
benzisothiazolone compound
ebsulfur (EbS), a
sulfur analogue of
ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-
protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and
NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the
enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and
trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular
reactive oxygen species.
Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of
reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei
infection in mice when used together with
nifurtimox. Altogether, EbS and EbS analogues disrupt the
trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against
African trypanosomiasis.