title: Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage.
abstract: The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies.
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Amanda Fortes
authors.initials: AF
authors.lastname: Francisco
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Shiromani
authors.initials: S
authors.lastname: Jayawardhana
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lewis
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville 3052, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville 3052, Australia.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville 3052, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Saunders
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Osuna-Cabello
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Drugs for Neglected Diseases Initiative (DNDi), 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Kelly
mesh_terms: D000818:Animals; D019540:Area Under Curve; D014355:Chagas Disease / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009547:Nifurtimox / Q000493:pharmacokinetics / Q000494:pharmacology; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome; D014344:Trypanocidal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C038307:fexinidazole; D009547:Nifurtimox; C009999:benzonidazole