**1. Introduction**

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No. 3, pp. 299-309.

226 Drug Discovery

*cules*, Vol. 1, No. 1, pp. 19-25.

Infectious diseases caused by parasites are a major threat for entire mankind, especially in the tropics. These infections are not only restricted to humans, they are also predominant in animal health. Just a few years ago infectious diseases caused by parasites were classified as an issue of the past. Due to the elevating level of drug resistance of these pathogens against the current chemotherapeutics, the need for new drugs became even more important. In particular parasitic diseases such as malaria, leishmaniasis, trypanosomiasis, amoebiasis, tri‐ chomoniasis, soil-transmitted helminthiasis, filariasis and schistosomiasis are major health problems, especially in "developing" areas (Renslo and McKerrow, 2006; Pal and Bandyo‐ padhyay, 2012). A variety of these parasitic diseases, which comprises the so called neglect‐ ed diseases Chagas disease, leishmaniasis, sleeping sickness, schistosomiasis, lymphatic filariasis, onchocerciasis and of course malaria (Chatelain and Ioset, 2011), are transmitted by vectors and therefore attempts to combat transmission became prominent. In contrast to the treatment of bacterial infections with antibiotics there are no "general" antiparasitic drugs. The use of a specific drug is dependent on the parasitic organism and therefore has to be individually chosen (Khaw et al., 1995).

Reactive oxygen species (ROS) and oxidative stress are the inevitable consequences of aero‐ bic metabolism, with partially reduced and highly reactive metabolites of O2 being formed in the mitochondria (Andreyev et al., 2005) or as by-products of other cellular sources such as the cytoplasm, the endoplasmatic reticulum, the plasma membrane and peroxisomes. Furthermore, environmental agents such as ionizing and UV radiation or xenobiotic expo‐ sure can generate intracellular ROS. O2 metabolites include superoxide anion (O2-) and hy‐ drogen peroxide (H2O2), formed by one- and two electron reductions of O2 or the highly reactive hydroxyl radical (‧ OH) which is formed in the presence of metal ions via Fenton

and/or Haber-Weiss reactions (Massimine et al., 2006). At physiologically low levels, ROS can function as second messenger in redox signaling, with H2O2 best providing the specifici‐ ty in its interaction with effectors in signaling processes (Forman et al., 2010). Balancing the generation and elimination of ROS maintains the proper function of redox-sensitive signal‐ ling proteins. However, severe increases of ROS induce oxidative modifications in the cellu‐ lar macromolecules DNA, proteins and lipids, this leading to a disruption of redox homeostasis and irreversible oxidative damage (Trachootham et al., 2008). Depending on the cellular context, the levels of ROS and the redox state of the cells, alterations of the deli‐ cate redox balance can promote cell proliferation and survival or induce cell death.

named redox-active antiparasitic drugs (Seeber et al., 2005) on which we will mainly focus

Oxidative Stress in Human Infectious Diseases – Present and Current Knowledge About Its Druggability

http://dx.doi.org/10.5772/53758

229

Leishmaniasis is caused by the protozoan flagellate *Leishmania* which is transmitted by sand‐ flies of the genus *Phlebotomus* (Sharma and Singh, 2008). There are several species of the ge‐ nus *Leishmania* which are known to cause this infectious disease. Leishmaniasis shows a broad spectrum of clinical manifestations and includes visceral, cutaneous and mucocutane‐ ous leishmaniasis. Whereas the two latter ones are not considered to be lethal (Herwaldt, 1999), infection with *Leishmania donovani/infantum* – resulting in kala azar or visceral leish‐ maniasis - can be lethal without treatment. Although treatment of leishmaniasis with che‐ motherapeutics is the only current option, drug resistance to first-line drugs is increasing which is accompanied by frequently occurring toxic side effects and by the high cost of treatment (Van Assche et al., 2011). Additionally, the small number of novel drugs com‐ bined with the low number of identified and subsequently validated number of *Leishmania* drug targets in clinical use, reveals an alarming situation for the current status in chemother‐ apy. The predominant target for the application of chemotherapy is the amastigote stage which proliferates intracellularly in tissue macrophages (Dedet et al., 2009), thereby hinder‐

Despite the fact that antimonials were already identified in 1921, they still remain the firstline treatment, although the precise mode of action is not known. But it is generally accepted that pentavalent antimonials (SbV) represent a pro-drug which is converted to trivalent anti‐ monials (SbIII) for antileishmanial activity. Recently it has been indicated that thiols act as re‐ ducing agents in this conversion. Furthermore, the participation of a unique parasite-specific trimeric glutathione transferase TDR1 in the activation of antimonial prodrugs has been sug‐

Treatment with antimonials requires parenteral administration and is accompanied by toxic side effects such as cardiac arrhythmia and acute pancreatitis (Sundar and Rai, 2002). Some studies have been carried out to investigate the activity mechanism of antimonials which correlates with an interference with the antioxidant defence system of the parasite: Trivalent antimonials decrease the thiol-reducing capacity of *Leishmania* by inducing an efflux of try‐ panothione. In contrast to *Leishmania*, mammalian cells depend on GSH to control their in‐ tracellular thiol-redox status. Here, ROS and oxidized cell components are efficiently reduced by GSH, thereby generating GSSG. The glutathione disulfide form can then be re‐ generated by the GSR (Monostori et al., 2009). In contrast, the redox metabolism of *Leishma‐ nia* relies on a modified GSH-system, *N*1,*N*8-bis(l-γ-glutamyl-l-hemicystinylglycyl)

**2. The role of the antioxidant system in** *Leishmania*

ing the accessibility of antileishmanial drugs to the pathogen.

within this chapter.

**3. Antimonials**

gested (Fyfe et al., 2012).

To maintain redox homeostasis and eliminate ROS, aerobes are equipped with enzymatic/ nonenzymatic antioxidants and metal sequestering proteins to either prevent or intercept the formation of pro-oxidants. Furthermore, protective mechanisms are put in place to re‐ pair and replace damaged macromolecules. Two central thiol/disulfide couples are involved in controlling the redox state of the cell: glutathione/glutathione disulfide (GSH/GSSG) is the major redox couple that determines the antioxidative capacity of cells, other redox couples include the active site dithiol/disulfide of thioredoxins (Trxred/Trxox) interacting with a differ‐ ent subset of proteins and thus forming a distinct but complementary redox system (Jones and Go, 2010).

Enzymatic antioxidants can be categorized into primary or secondary antioxidants, the first reacting directly with pro-oxidants (e.g. catalase, superoxide dismutase), the latter are in‐ volved in the regeneration of low molecular weight antioxidant species (Halliwell, 1999). Here, the reduced state of GSSG and Trx-enzymes is restored by the glutathione reductase (GSR) and the Trx reductase using electrons obtained from NADPH. Additionally glutare‐ doxins (Glrx) utilize GSH for the reduction of intracellular disulfides (Fernandes and Holmgren, 2004). While Trx, Trx reductase and Trx peroxidase (peroxiredoxin, Prx) consti‐ tute the Trx-system, the versatile GSH-system includes enzymes required for GSH synthesis and recycling, for its use in metabolism, in defense against ROS-induced damage and in a multitude of detoxification processes. Furthermore, for normal GSH turnover and disposi‐ tion of GSH-conjugated metabolites and xenobiotics, export from the cell is required that is carried out by GSH efflux transporters and pumps (Sies, 1999) (Fig. 1).

In spite of the diversity of parasites, all are faced with similar biological problems that are related to their lifestyle. Besides coping with ROS levels generated from intrinsic sources, all have to deal with the oxidative stress imposed by the host´s immune response. Furthermore, parasites are faced with ROS that are produced during the epithelial innate immune re‐ sponse of their vector, by vector-resident gut bacteria (Cirimotich et al., 2011) or during mel‐ anotic encapsulation processes (Kumar et al., 2003).

Since the redox system plays such a fundamental and indispensable role for parasite surviv‐ al within their host (Massimine et al., 2006), drugs that either promote ROS generation or inhibit cellular antioxidant systems will lead to redox imbalance by pushing ROS levels above a certain threshold level that will ultimately lead to parasite death (Müller et al., 2003). In general, drugs that target vital redox reactions or promote oxidative stress are named redox-active antiparasitic drugs (Seeber et al., 2005) on which we will mainly focus within this chapter.
