Depression of Plasmodium falciparum dihydroorotate dehydrogenase activity in in vitro culture by tetracycline

Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite

“…Unique structural features of the parasite cytochrome b a were speculated as being responsible for the therapeutic value of some of the hydroxynaphthoquinones as antimalarials (16). Because malarial mitochondria do not seem to contribute much to the ATP pool, it has long been suggested that the main purpose for these organelles was to dispose of electrons generated by dihydroorotate dehydrogenase (7)(8)(9), an essential enzyme in pyrimidine biosynthesis. Since the parasites are unable to salvage pyrimidines, inhibition of dihydroorotate dehydrogenase has been suggested as the reason for antimalarial activity of compounds such as atovaquone (43).…”

“…This observation is counter to the classical effect of CCCP where a collapsed membrane potential leads to a release from respiration control over electron transport, resulting in an increased rate of O 2 consumption. different drugs were tested: atovaquone, a new broad spectrum antiparasitic drug shown to inhibit the bc 1 complex of the malarial parasite (24); tetracycline, an antibiotic thought to inhibit organellar protein synthesis (9,25); and chloroquine, a drug likely to affect nonmitochondrial target(s) (26 -29). Representative fluorescence histograms of infected red blood cells in the presence and absence of antimalarial compounds are presented in Fig.…”

“…It is generally believed that glycolysis is the main source of ATP in erythrocytic stages of malarial parasites with little or no contribution by mitochondria to the cellular ATP pool (1,2). A lack of tricarboxylic acid cycle enzymes (3)(4)(5)(6) and an acristate mitochondrial morphology has led to the suggestion that mitochondria in malaria parasite act mainly to serve as an electron disposal sink for dihydroorotate dehydrogenase, a critical enzyme in pyrimidine biosynthesis (7)(8)(9). It is well established through studies in other systems that, in addition to oxidative phosphorylation, mitochondria are also central to many other physiological activities such as the metabolism of molecules such as amino acids, lipids, and heme, as well as intracellular Ca 2ϩ homeostasis (10).…”

Antibiotics for prophylaxis of Plasmodium falciparum infections: in vitro activity of doxycycline against Senegalese isolates.

“…Tetracycline acts on the mitochondrion 26 and depresses the activity of dihydroorotate dehydrogenase of the pyrimidine pathway in P. falciparum, 14 presumably due to inhibition of enzyme protein synthesis. Doxyxycline reduces levels of malaria nucleoside 5Ј-triphosphates and deoxynucleoside 5Ј-triphosphates 27 and has shown inhibitory effects against pre-erythrocytic stages.…”

“…10 Experimental observations obtained in vitro 11,12 and in clinical studies 13 showed antimalarial activity of tetracycline and its derivatives. Tetracycline depresses the activity of dihydroorotate dehydrogenase of the pyrimidine pathway in P. falciparum, 14 presumably due to inhibition of enzyme protein synthesis. Daily doxycycline has been shown to be an effective causal chemoprophylactic in Thailand, 15 Indonesia, 16 and Kenya.…”