|Crispim M, Verdaguer IB, Zafra CA, Katzin AM (2019) Effects of atovaquone and 4-nitrobenzoate on Plasmodium falciparum respiration. MitoFit Preprint Arch doi:10.26124/mitofit:ea19.MiPSchool.0007.v2.|
Although atovaquone is one of the newest antimalarial compounds discovered, resistant parasites have already been reported1. Atovaquone mechanism of action is established to be the competition with ubiquinol (UQH2) for the bc1 union at mitochondrial cytochrome bc1 complex and preventing the parasite from maintaining an oxidized ubiquinone (UQ) pool, essential for the DHODH activity and consequently for the pyrimidine's biosynthesis. In this sense, possible inhibitors of the ubiquinone biosynthesis pathway would be candidates by stimulating the effects of atovaquone. 4-nitrobenzoate (4-NB) is a well-known inhibitor of 4HPT (4-hydroxybenzoate polyprenyltransferase), the first enzyme of UQ biosynthesis. 4-NB also showed an important effect on reducing the UQs pool in P. falciparum. Herein is presenting the effect of atovaquone and 4-NB on parasitic respiration UQ biosynthesis. The purpose of this study was to better understand the atovaquone mechanism of action in a molecular scale, drug target potential of UQ biosynthesis. Oxygen consumption assays revealed 4-NB potentiates atovaquone mitochondrial effects and showed itself the ability to decrease the respiration rate.
- Extended abstract
• Bioblast editor: Iglesias-Gonzalez J
Crispim Marcell(1) , Verdaguer IB(1), Zafra CA(1), Katzin AM(1)
- Dept. of Parasitology, Laboratório de Malária, Univ. of Sao Paulo, Sao Paulo, Brazil. Av. Prof. Lineu Prestes, 1374 - Edifício Biomédicas II - Cidade Universitária "Armando Salles Oliveira" - CEP: 05508-000.- firstname.lastname@example.org
- Staines HM, Burrow R, Teo BH, Chis Ster I, Kremsner PG, Krishna S (2018) Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis. J Antimicrob Chemother 73(3):581-595.
- Trager W, Jensen JB (1976) Human malaria parasites in continuous culture. J Parasitol 91(3):484-6.
- Tonhosolo R, Gabriel HB, Matsumura HY, Cabral FJ, Yamamoto MM, D’Alexandri FL, Sussmann RAC, Belmonte R, Peres VJ, Crick DC, Wunderlich G, Kimura EA, Katzin AM (2010) Intraerythrocytic stages of Plasmodium falciparum biosynthesize menaquinone. FEBS Lett 584: 4761–4768.
- Lambros C, Vanderberg JP (1979) Synchronization of Plasmodium falciparum erythrocytic stages in culture. J. Parasitol 65: 418–20.
- Murphy AD, Doeller JE, Hearn B, Lang-Unnasch N (1997) Plasmodium falciparum: cyanide-resistant oxygen consumption, Exp Parasitol 87: 112–120.
- Forsman U, Sjöberg M, Turunen M, Sindelar PJ (2010) 4-Nitrobenzoate inhibits coenzyme Q biosynthesis in mammalian cell cultures. Nat Chem Biol 6(7):515-7.