Antimalarial properties of bredinin. Prediction based on identification of differences in human host-parasite purine metabolism.

Abstract

A B S T R A C T Human malaria parasites (Plasmodium falciparum) grown in continuous erythrocyte culture utilize hypoxanthine for synthesis of both guanosine and adenosine nucleotides. Unlike the mature human erythrocyte, the malaria parasite depends on a constant supply of guanylates, primarily for synthesis of nucleic acids. This parasite specific requirement for guanylates led us to predict that a block in the hypoxanthine to quanosine monophosphate pathway would be selectively lethal to the parasite. Bredinin (4 -carbamoyl-1 -,B-D -ribofuranyosyl -imidazolium -5-olate) inhibited the synthesis of guanosine monophosphate from inosine monophosphate by parasitized erythrocytes. This block in guanylate synthesis was fatal to both a drug-sensitive (FCR-3) and a drug-resistant (VNS) strain of the malaria parasite at a bredinin concentration of 50 MM, arresting growth of the parasite at the trophozoite stage of development. These studies emphasize the essential role of guanylates and their synthesis from hypoxanthine in the metabolism of malaria parasite. They further suggest that bredinin or similar agents that selectively interfere with parasite guanylate metabolism may have potential for antimalarial chemotherapy.

IMP Dehydrogenase: Structure, Mechanism, and Inhibition

“…Nevertheless, IMPDH is emerging as a promising target in several systems. The IMPDH inhibitors MPA and/or mizoribine inhibit the growth of Tritrichomonas foetus 50, Candida albicans 51, Cryptosporidium parvum 52, Leishmania donovani 53, Trypanosoma brucei 54, Staphylococcus aureus 55, Eimeria tenella 56 and Plasmodium falciparum 57. As described in section 7.5, parasite-selective IMPDH inhibitors have recently been reported 58.…”

The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors

“…Mycophenolic acid also blocks proliferation of Staphylococcus aureus [15, 16] as well as the eukaryotic pathogens Candida albicans [17], Pneumocystis carinii ; [18], Leishmania donovani [19], Trypanosoma brucei gambienese [20], Eimeria tenella [21] and Cryptosporidium parvum [22]. Mizoribine, another natural product IMPDH inhibitor, blocks the growth of C. albicans [17] and Plasmodium falciparum [23]. Unfortunately, both MPA and mizoribine are potent inhibitors of mammalian IMPDHs, and so can only serve to provide proof of concept.…”

Kinetic and biochemical characterization ofPlasmodium falciparumGMP synthetase

“…Also, both human erythrocytes and P. falciparum lack guanosine kinase, eliminating the possibility of generating GMP from guanosine. The potent antimalarial activities of mycophenolic acid, an inhibitor of IMPDH, and bredinin, an inhibitor of both IMPDH and GMPS, underscore the necessity of GMPS for the survival of intra-erythrocytic P. falciparum [5,6]. McConkey [7] reported the DNA sequence of PfGMPS (P. falciparum GMPS) and the absence of any introns in the gene.…”