Mercaptopyridine-N-oxide, an NADH-fumarate reductase inhibitor, blocks Trypanosoma cruzi growth in culture and in infected myoblasts.
The enzyme NADH-fumarate reductase is not found in mammalian cells but it is present in several parasitic protozoa including Trypanosoma cruzi, the parasite that causes Chagas' disease. This study shows that the drug 2-mercaptopyridine-N-oxide (MPNO) inhibits NADH-fumarate reductase purified from T. cruzi (ID50 = 35 microM). When added to intact cells, MPNO inhibited the growth of T. cruzi epimastigotes in culture (ID50 = 0.08 microM) as well as the infection of mammalian myoblasts by T. cruzi trypomastigotes (ID50 = 20 microM). At a concentration of 2.4 microM, MPNO also inhibited the growth of amastigotes (intracellular dividing forms) in cultured mammalian myoblasts. Supplementation of culture media with 5 mM succinate, the product of fumarate reductase, partially protected against the inhibition of the growth of epimastigotes by MPNO. Moreover, MPNO inhibited the accumulation of succinate in cultures of epimastigotes, as measured by high performance liquid chromatography. Although MPNO may have other intracellular targets in addition to fumarate reductase, these results support the hypothesis that compounds which inhibit the enzyme fumarate reductase may be potential chemotherapeutic agents against Chagas' disease.
Turrens
J F
JF
Department of Biomedical Sciences, University of South Alabama, Mobile 36688-0002, USA. jturrens@jaguar1.usouthal.edu
Newton
C L
CL
Zhong
L
L
Hernandez
F R
FR
Whitfield
J
J
Docampo
R
R
D000818:Animals; D003470:Culture Media; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009132:Muscles / Q000166:cytology / Q000469:parasitology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013386:Succinates / Q000378:metabolism; D013871:Thiones; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
D003470:Culture Media; D004791:Enzyme Inhibitors; D011725:Pyridines; D013386:Succinates; D013871:Thiones; D014344:Trypanocidal Agents; C008704:pyrithione; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C020155:fumarate reductase (NADH)