Products & Services
Applications

Applications

Nanopore sequencing offers advantages in all areas of research. Our offering includes DNA sequencing, as well as RNA and gene expression analysis and future technology for analysing proteins.

Learn about applications
View all Applications
Resources
News Explore
Contact
Back

Mitochondrial heteroplasmy is responsible for Atovaquone drug resistance in Plasmodium falciparum

Publication

Date: 9th December 2017 | Source: BioRxiv

Authors: Sasha V Siegel, Andrea V Rivero, Swamy R Adapa, ChengQi Wang, Roman Manetsch, Rays HY Jiang, Dennis E Kyle.

Malaria is the most significant parasitic disease affecting humans, with 212 million cases and 429,000 deaths in 20151, and resistance to existing drugs endangers the global malaria elimination campaign. Atovaquone (ATO) is a safe and potent antimalarial drug that acts on cytochrome b (cyt. b) of the mitochondrial electron transport chain (mtETC) in Plasmodium falciparum, yet treatment failures result in resistance-conferring SNPs in cyt. b. Herein we report that rather than the expected de novo selection of resistance, previously unknown mitochondrial diversity is the genetic mechanism responsible for resistance to ATO, and potentially other cyt. b targeted drugs. We found that P. falciparum harbors cryptic cyt. b. Y268S alleles in the multi-copy (~22 copies) mitochondrial genome prior to drug treatment, a phenomenon known as mitochondrial heteroplasmy. Parasites with cryptic Y268S alleles readily evolve into highly resistant parasites with >95% Y268S copies under in vitro ATO selection. Further we uncovered high mitochondrial diversity in a global collection of 1279 genomes in which heteroplasmic polymorphisms were >3-fold more prevalent than homoplasmic SNPs. Moreover, significantly higher mitochondrial genome copy number was found in Asia (e.g., Cambodia) versus Africa (e.g., Ghana). Similarly, ATO drug selections in vitro induced >3-fold mitochondrial copy number increases in ATO resistant lines. Hidden mitochondrial diversity is a previously unknown mechanism of antimalarial drug resistance and characterization of mitochondrial heteroplasmy will be of paramount importance in combatting resistance to antimalarials targeting the electron transport chain.

Read the full text

Recommended for you

Open a chat to talk to our sales team
FAQs

FAQs

Search