Poster Presentation First Malaria World Congress 2018

Drug resistance in malaria: investigating the mechanisms of resistance to doxycycline and artemisinin (#419)

Emily M Crisafulli 1 , Natalie J Spillman 2 , Leann Tilley 1 , Stuart A Ralph 1
  1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
  2. School of BioSciences, The University of Melbourne, Melbourne, Australia

Resistance has developed to most antimalarial drugs. We aim to better understand the molecular mechanisms that underpin resistance to artemisinin (ART) and doxycycline, the leading drugs for malaria treatment and prevention, respectively.

Reduced ART sensitivity has emerged in South-East Asia and is associated with mutations in K13, the most prevalent of which is a C580Y mutation. A disulphide bond forms between C580 and another cysteine, C532, in one of the experimentally determined structures of K13. We hypothesise that these cysteine residues act as an oxidative stress switch that modulates the function of K13, and that the C580Y mutation mediates ART sensitivity by preventing the formation of this bond. I will generate several K13 C580 mutations, determine their sensitivity to ART and measure the abundance of K13 via label-free quantification.

The mechanisms of resistance to doxycycline will also be investigated. Whilst doxycycline resistance is not yet widespread, it is crucial to identify potential resistance markers. An increased copy number of the Plasmodium genes pfmdt and pftetQ are associated with reduced doxycycline sensitivity, in addition to polymorphisms in pftetQ. We aim to clarify the mechanism of these putative resistance proteins by mutation and genetic modulation, and by subsequently assessing doxycycline sensitivity.