Within-Host Selection of Drug Resistance in a Mouse Model Reveals Dose-Dependent Selection of Atovaquone Resistance Mutations
| Autor: | Andy I. M. Hoepelman, Sangkot Marzuki, Josephine E. Siregar, Suci Nuralitha, Jessica Roelands, Jan Verhoef, Lydia S. Murdiyarso, Din Syafruddin |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Plasmodium berghei 030106 microbiology Drug Resistance Drug resistance Biology Pharmacology 03 medical and health sciences Antimalarials Mice Quinone binding Therapeutic index Within-host selection of atovaquone resistance Mechanisms of Resistance medicine Journal Article Animals Medication Errors Pharmacology (medical) Drug Dosage Calculations Gene Atovaquone Mice Inbred BALB C Dose-dependent selection Cytochromes b medicine.disease biology.organism_classification Phenotype Repeated incomplete treatment Malaria Infectious Diseases Mouse malaria model medicine.drug Repeated inadequate treatment |
| Zdroj: | Antimicrobial Agents and Chemotherapy, 61(5). American Society for Microbiology |
| ISSN: | 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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