Drug resistance human parasites

Several of the pathogenic human parasites (.Plasmodium, Leishmania, and Trypanosoma) often develop resistance to prophylactic and therapeutic compounds, such as quinolines, naphthoquinones, sesquiterpene lactones, and others. The underl)dng bases are membrane glycoproteins that are orthologous to the human P-gp, which can be induced and activated. The search for compounds that can reverse the drug resistance in parasites, also includes alkaloids (63). 

Chloroquine has been the drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s, but its usefulness against P falciparum has been seriously compromised by drug resistance. It remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites. 

Helminths, especially parasitic nematodes, cause severe health problems in humans and domestic animals. Although several classes of anthelmintics are commercially available, their suboptimal therapeutic spectrum and diminished activity due to the development of drug resistant... 

Scientists at the University of Michigan Medical School, in collaboration with those at the Indian Institute of Science in Bangalore, have carried out tests on curcumin that show it to inhibit the drug-resist-ant forms of malaria and reported their findings in the Journal of Biological Chemistry in December 2004. Mice infected with the related parasite, Plasmodium falciparum, which causes rodent malaria, were fed curcumin and this reduced the number of parasites in the blood by as much as 90%, and completely protected more than a quarter of mice to whom it was given. Whether it could be a treatment for human malarial infection remains to be seen. 

Anthelmintics are drugs that act locally to expel worms from the GI tract or systemicaUy to eradicate adult helminths or developmental forms that invade organs and tissues. Because metazoan parasites generally are long-lived and have relatively complex life cycles, acquired resistance to anthelmintics in humans is not a major factor limiting clinical efficacy. The extensive use of anthelmintics in veterinary medicine ensures that the potential of drug resistance among helminths in humans cannot be discounted. 

The BZAs inhibit microtubule polymerization by binding to p-tubulin. The selective toxicity of these agents likely results because the BZAs bind parasite fi-tubulin with much higher affinity than they do the mammalian protein. Drug resistance in nematodes may involve expression of a mutated fftubulin. There is no evidence of emerging resistance among human nematodes. 

Malaria is still one of the most prevalent protozoan diseases in the world. The mosquito infects the human and the parasite passes through two phases. The tissue phase causes no clinical symptoms in the human and the erythrocytic phase invades red blood cells and causes chills, fever, and sweating. In the United States the 1000 cases reported annually are almost all from international travel. Quinine was the only antimalarial drug from 1820 to the early 1940s when synthetic antimalarial drugs were developed. Chloroquine is commonly prescribed. If drug resistance develops quinine is used in combination with an antibiotic such as tetracycline. 

It was observed earlier that over expression of human N-terminal domain in yeast confers resistance to high concentrations of etoposide. The observed phenotype was proposed to be due to the competition of the excess of the N-terminal domain with the frill length enzyme for a limiting pool of inhibitor. So future challenge in the parasite topoisomerase II would be to develop drug resistant parasite strains and to see what causes this resistance and also to check what effect the individual domains of the enzyme have on the drug protein interaction in the context of the full-length enzyme. 

The human malaria parasite Plasmodium falciparum expresses two neutral zinc-aminopeptidases, PfA-Ml and PfA-M17, which function in regulating the intracellular pool of amino acids required for parasite growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. As a result of the rapid emergence of drug-resistant parasites, blocking these peptidases with potent inhibitors has been proposed as a potential new antimalarial therapy. The simple phosphinic dipeptide 61 (Table 1) was reported to inhibit PfA-M17 with a Ki value of 80 nM [130]. 

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