Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection
Abstract Background To study within-host selection of resistant parasites, an important factor in the development of resistance to anti-malarial drugs, a mouse model of repeated interrupted malaria treatment (RIT) has been developed. The characteristics of within host selection of resistance to atov...
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ftdoajarticles:oai:doaj.org/article:bf581bcfcf43415e96014f94fc8fa842 2023-05-15T15:15:59+02:00 Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection Suci Nuralitha Josephine E. Siregar Din Syafruddin Andy I. M. Hoepelman Sangkot Marzuki 2017-05-01T00:00:00Z https://doi.org/10.1186/s12936-017-1860-6 https://doaj.org/article/bf581bcfcf43415e96014f94fc8fa842 EN eng BMC http://link.springer.com/article/10.1186/s12936-017-1860-6 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-017-1860-6 1475-2875 https://doaj.org/article/bf581bcfcf43415e96014f94fc8fa842 Malaria Journal, Vol 16, Iss 1, Pp 1-6 (2017) Within-host selection of atovaquone resistance Mouse malaria model Plasmodium yoelii Repeated interrupted treatment Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2017 ftdoajarticles https://doi.org/10.1186/s12936-017-1860-6 2022-12-31T00:14:00Z Abstract Background To study within-host selection of resistant parasites, an important factor in the development of resistance to anti-malarial drugs, a mouse model of repeated interrupted malaria treatment (RIT) has been developed. The characteristics of within host selection of resistance to atovaquone and pyrimethamine in Plasmodium yoelii was examined in such a model. Methods Treatment of P. yoelii infected mice, with atovaquone or pyrimethamine, was started at parasitaemia level of 3–5%, interrupted when reduced to less than 0.4%, and restarted following parasitaemia recovery to the initial level. Treatment cycles were repeated until stable phenotype resistance was observed. Results Plasmodium yoelii rapidly developed resistance to atovaquone (2.75 ± 1.06 cycles) and to pyrimethamine (5.4 ± 0.89 cycles) under RIT. A dose dependent phenomenon in the selection of atovaquone resistance mutations was observed. All mutations that underlie resistance to therapeutic doses of 0.3–1.44 mg kg−1 BW were found to be in the Qo2 domain of the cytochrome b gene (I258M, F267I/L/S, L271V, K272R, L271V and K272R). Those associated with lower doses of 0.01–0.03 mg kg−1 BW were in the Qo1 domain (M133I and T139S). The resistance mutations occurred at four of the 16 atovaquone putative drug binding sites suggested in P. falciparum. Conclusions RIT of P. yoelii infected mice led to rapid development of resistance to atovaquone and pyrimethamine. The dose dependent selection of resistance mutants to atovaquone observed during RIT might reflect the outcome of two different causes of malaria treatment failure in human, repeated incomplete treatment with therapeutic dose and repeated inadequate treatment associated with sub-therapeutic dose, and need to be systematically investigated. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 16 1 |
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English |
topic |
Within-host selection of atovaquone resistance Mouse malaria model Plasmodium yoelii Repeated interrupted treatment Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
spellingShingle |
Within-host selection of atovaquone resistance Mouse malaria model Plasmodium yoelii Repeated interrupted treatment Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Suci Nuralitha Josephine E. Siregar Din Syafruddin Andy I. M. Hoepelman Sangkot Marzuki Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection |
topic_facet |
Within-host selection of atovaquone resistance Mouse malaria model Plasmodium yoelii Repeated interrupted treatment Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background To study within-host selection of resistant parasites, an important factor in the development of resistance to anti-malarial drugs, a mouse model of repeated interrupted malaria treatment (RIT) has been developed. The characteristics of within host selection of resistance to atovaquone and pyrimethamine in Plasmodium yoelii was examined in such a model. Methods Treatment of P. yoelii infected mice, with atovaquone or pyrimethamine, was started at parasitaemia level of 3–5%, interrupted when reduced to less than 0.4%, and restarted following parasitaemia recovery to the initial level. Treatment cycles were repeated until stable phenotype resistance was observed. Results Plasmodium yoelii rapidly developed resistance to atovaquone (2.75 ± 1.06 cycles) and to pyrimethamine (5.4 ± 0.89 cycles) under RIT. A dose dependent phenomenon in the selection of atovaquone resistance mutations was observed. All mutations that underlie resistance to therapeutic doses of 0.3–1.44 mg kg−1 BW were found to be in the Qo2 domain of the cytochrome b gene (I258M, F267I/L/S, L271V, K272R, L271V and K272R). Those associated with lower doses of 0.01–0.03 mg kg−1 BW were in the Qo1 domain (M133I and T139S). The resistance mutations occurred at four of the 16 atovaquone putative drug binding sites suggested in P. falciparum. Conclusions RIT of P. yoelii infected mice led to rapid development of resistance to atovaquone and pyrimethamine. The dose dependent selection of resistance mutants to atovaquone observed during RIT might reflect the outcome of two different causes of malaria treatment failure in human, repeated incomplete treatment with therapeutic dose and repeated inadequate treatment associated with sub-therapeutic dose, and need to be systematically investigated. |
format |
Article in Journal/Newspaper |
author |
Suci Nuralitha Josephine E. Siregar Din Syafruddin Andy I. M. Hoepelman Sangkot Marzuki |
author_facet |
Suci Nuralitha Josephine E. Siregar Din Syafruddin Andy I. M. Hoepelman Sangkot Marzuki |
author_sort |
Suci Nuralitha |
title |
Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection |
title_short |
Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection |
title_full |
Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection |
title_fullStr |
Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection |
title_full_unstemmed |
Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection |
title_sort |
within-host selection of drug resistance in a mouse model of repeated interrupted treatment of plasmodium yoelii infection |
publisher |
BMC |
publishDate |
2017 |
url |
https://doi.org/10.1186/s12936-017-1860-6 https://doaj.org/article/bf581bcfcf43415e96014f94fc8fa842 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 16, Iss 1, Pp 1-6 (2017) |
op_relation |
http://link.springer.com/article/10.1186/s12936-017-1860-6 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-017-1860-6 1475-2875 https://doaj.org/article/bf581bcfcf43415e96014f94fc8fa842 |
op_doi |
https://doi.org/10.1186/s12936-017-1860-6 |
container_title |
Malaria Journal |
container_volume |
16 |
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1 |
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1766346307348201472 |