Chemotherapy - Control of Protozoan Parasites

CHEMOTHERAPY

The origins of chemotherapy are closely linked to the development of antiparasitic agents, but there has been slow progress in the development of new and novel antiprotozoal agents over the past 30 years. Recently, with the support of the WHO and government sponsored research, new antiparasitic drugs are slowly coming into the market. Interestingly there are still a number of protozoan parasite infections such as cryptosporidiosis for which there is no effective treatment.

Mechanisms of action and selective toxicity

For many of the commonly used antiprotozoal drugs the modes of action and mechanisms of selective toxicity are well understood, although for some the precise mechanism remains unclear. The most common antiprotozoal drugs and their modes of action are shown in Table 6.1.

Considering the drugs in relation to modes of action, dapsone and the sulphonamides block the biosynthesis of tetrahydrofolate by inhibiting dihydropteroate synthetase, while the 2,4diaminopyrimidines (proguanil and pyrimethamine) block the same pathway but at a later step catalysed by dihydrofolate reductase.

The drugs that interfere with nucleic acid synthesis include those that bind to the DNA and intercalate with it such as chloroquine, mefloquine and quinine, and also pentamidine, which is unable to intercalate but probably interacts ionically. Other compounds such as benznidazole and metronidazole may alkylate DNA through activation of nitro groups via a one-electron reduction step. Several of these compounds, however, including chloroquine, mefloquine, quinine and metronidazole, have more than one potential mode of action. Chloroquine, for example, inhibits the enzyme haem polymerase, which functions to detoxify the cytotoxic molecule haem that is generated during the degradation of haemoglobin. Metronidazole is reduced in the parasite cell and forms a number of cytotoxic intermediates, which can cause damage not only to DNA but also to membranes and proteins.

Tetracycline targets protein synthesis in Plasmodium via a similar mechanism to that seen in bacteria: inhibition of chain elongation and peptide bond formation. Eflornithine interferes with the metabolism of the amino acid ornithine in T. brucei gambiense by acting as a suicide substrate for the enzyme ornithine decarboxylase.

Albendazole has recently been shown to have significant anti-giardial activity, although its mode of action is unclear. In Leishmania, amphotericin B binds to ergosterol in the membrane making it leaky to ions and small molecules (e.g. amino acids), while the anti  protozoal drugs atovaquone and primaquine bind to the cytochrome bc ₁ complex and inhibit electron flow. The anti-trypanosomal drug melarsaprol is most likely to act by blocking glycolytic kinases, especially the cytoplasmic pyruvate kinase, although it may also disrupt the reduction of trypanothione.

Drug resistance

As with bacteria, drug resistance in some parasites such as Plasmodium is a major problem and tends to appear where chemotherapy has been used extensively. This problem is exacerbated by the fact there are so few drugs available for the control of some parasites, which utilize the same five basic resistance mechanisms that are displayed by bacteria: (1) metabolic inactivation of the drug; (2) use of efflux pumps; (3) use of alternative metabolic pathways; (4) alteration of the target; (5) elevation of the amount of target enzyme.