Within-host selection of drug resistance in a mouse model reveals dose-dependent selection of atovaquone resistance mutations

Suci Nuralitha, Lydia S. Murdiyarso, Josephine E. Siregar, Din Syafruddin, Jessica Roelands, Jan Verhoef, Andy I.M. Hoepelman, Sangkot Marzuki

Research output: Contribution to journalArticle

Abstract

The evolutionary selection of malaria parasites within an individual host plays a critical role in the emergence of drug resistance. We have compared the selection of atovaquone resistance mutants in mouse models reflecting two different causes of failure of malaria treatment, an inadequate subtherapeutic dose and an incomplete therapeutic dose. The two models are based on cycles of insufficient treatment of Plasmodium berghei-infected mice: repeated inadequate treatment associated with a subtherapeutic dose (RIaT) (0.1 mg kg-1 of body weight) and repeated incomplete treatment with a therapeutic dose (RIcT) (14.4 mg kg-1 of body weight). The number of treatment cycles for the development of a stable resistance phenotype during RIaT was 2.00 - 0.00 cycles (n - 9), which is not statistically different from that during RIcT (2.57 - 0.85 cycles; combined n - 14; P - 0.0591). All mutations underlying atovaquone resistance selected by RIaT (M133I, T142N, and L144S) were found to be in the Qo1 (quinone binding 1) domain of the mitochondrial cytochrome b gene, in contrast to those selected by RIcT (Y268N/C, L271V, K272R, and V284F) in the Qo2 domain or its neighboring sixth transmembrane region. Exposure of mixed populations of resistant parasites from RIaT to the higher therapeutic dose of RIcT revealed further insights into the dynamics of within-host selection of resistance to antimalarial drugs. These results suggest that both inadequate subtherapeutic doses and incomplete therapeutic doses in malaria treatment pose similar threats to the emergence of drug resistance. RIcT and RIaT could be developed as useful tools to predict the potential emergence of resistance to newly introduced and less-understood antimalarials.

Original languageEnglish
Article numbere01867
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number5
DOIs
Publication statusPublished - 1 May 2017

Fingerprint

Atovaquone
Drug Resistance
Malaria
Mutation
Antimalarials
Parasites
Body Weight
Plasmodium berghei
Cytochromes b
Therapeutics
Treatment Failure
Phenotype
Population
Genes

Keywords

  • Dose-dependent selection
  • Mouse malaria model
  • Repeated inadequate treatment
  • Repeated incomplete treatment
  • Within-host selection of atovaquone resistance

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Within-host selection of drug resistance in a mouse model reveals dose-dependent selection of atovaquone resistance mutations. / Nuralitha, Suci; Murdiyarso, Lydia S.; Siregar, Josephine E.; Syafruddin, Din; Roelands, Jessica; Verhoef, Jan; Hoepelman, Andy I.M.; Marzuki, Sangkot.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 5, e01867, 01.05.2017.

Research output: Contribution to journalArticle

Nuralitha, Suci ; Murdiyarso, Lydia S. ; Siregar, Josephine E. ; Syafruddin, Din ; Roelands, Jessica ; Verhoef, Jan ; Hoepelman, Andy I.M. ; Marzuki, Sangkot. / Within-host selection of drug resistance in a mouse model reveals dose-dependent selection of atovaquone resistance mutations. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 5.
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