Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage

Amanda Fortes Francisco, Shiromani Jayawardhana, Michael D. Lewis, Karen L. White, David M. Shackleford, Gong Chen, Jessica Saunders, Maria Osuna-Cabello, Kevin D. Read, Susan A. Charman, Eric Chatelain, John M. Kelly (Lead / Corresponding author)

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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.

Original languageEnglish
Article number35351
Pages (from-to)1-11
Number of pages11
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 17 Oct 2016

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Trypanosoma cruzi
Nifurtimox
Sulfones
Chagas Disease
Infection
Pharmaceutical Preparations
Latin America
Therapeutics
Insects
Immune System
Parasites
fexinidazole
benzonidazole

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Francisco, A. F., Jayawardhana, S., Lewis, M. D., White, K. L., Shackleford, D. M., Chen, G., ... Kelly, J. M. (2016). Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage. Scientific Reports, 6, 1-11. [35351]. https://doi.org/10.1038/srep35351
Francisco, Amanda Fortes ; Jayawardhana, Shiromani ; Lewis, Michael D. ; White, Karen L. ; Shackleford, David M. ; Chen, Gong ; Saunders, Jessica ; Osuna-Cabello, Maria ; Read, Kevin D. ; Charman, Susan A. ; Chatelain, Eric ; Kelly, John M. / Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage. In: Scientific Reports. 2016 ; Vol. 6. pp. 1-11.
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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.",
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note = "This work was supported by the Drugs for Neglected Diseases initiative (DNDi), an Australian Research Council Linkage Project grant (LP140100560) and Wellcome Trust awards (092340MF and 105021). For this project, DNDi received financial support from: Department for International Development (DFID), UK; Federal Ministry",
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Francisco, AF, Jayawardhana, S, Lewis, MD, White, KL, Shackleford, DM, Chen, G, Saunders, J, Osuna-Cabello, M, Read, KD, Charman, SA, Chatelain, E & Kelly, JM 2016, 'Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage', Scientific Reports, vol. 6, 35351, pp. 1-11. https://doi.org/10.1038/srep35351

Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage. / Francisco, Amanda Fortes; Jayawardhana, Shiromani; Lewis, Michael D.; White, Karen L.; Shackleford, David M.; Chen, Gong; Saunders, Jessica; Osuna-Cabello, Maria; Read, Kevin D.; Charman, Susan A.; Chatelain, Eric; Kelly, John M. (Lead / Corresponding author).

In: Scientific Reports, Vol. 6, 35351, 17.10.2016, p. 1-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage

AU - Francisco, Amanda Fortes

AU - Jayawardhana, Shiromani

AU - Lewis, Michael D.

AU - White, Karen L.

AU - Shackleford, David M.

AU - Chen, Gong

AU - Saunders, Jessica

AU - Osuna-Cabello, Maria

AU - Read, Kevin D.

AU - Charman, Susan A.

AU - Chatelain, Eric

AU - Kelly, John M.

N1 - This work was supported by the Drugs for Neglected Diseases initiative (DNDi), an Australian Research Council Linkage Project grant (LP140100560) and Wellcome Trust awards (092340MF and 105021). For this project, DNDi received financial support from: Department for International Development (DFID), UK; Federal Ministry

PY - 2016/10/17

Y1 - 2016/10/17

N2 - 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.

AB - 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.

U2 - 10.1038/srep35351

DO - 10.1038/srep35351

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VL - 6

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EP - 11

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

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