Oral Presentation First Malaria World Congress 2018

Transporters as determinants of drug resistance in the malaria parasite. (#137)

Sarah H Shafik 1 , Sashika N Richards 1 , Adele M Lehane 1 , Robert L Summers 1 2 , Rowena E Martin 1
  1. Australian National University, Acton, ACT, Australia
  2. Harvard T.H. Chan School of Public Health, Boston, MA, United States of America

Transporters mediate the movement of ions, nutrients, and waste products across the membranes of a cell and are central to its biochemistry and physiology.  Proteins of this type also serve as drug targets and/or mediators of drug transport and hence play key roles in the phenomenon of drug resistance.  The malaria parasite has a limited repertoire of transporters, with only ~2.4% of its genes encoding membrane transport proteins [1,2].  However, a significant number of these transporters have been identified as determinants of drug resistance.  For example, the Malaria Drug Accelerator (MalDA) Consortium recently identified the genetic determinants of the parasite’s resistance to ~50 of the candidate antimalarial drugs in the development pipeline [3].  Our analysis of this ‘resistome & druggable genome’ revealed that 53% of these genes encode membrane transport proteins, which brings the number of transporters implicated in antimalarial drug resistance to 24.  The determinants detected by the MalDA Consortium included the ‘chloroquine resistance transporter’ (PfCRT) and the ‘multidrug resistance protein 1’ (PfMDR1) – which were originally identified for their roles in conferring chloroquine resistance, but are now known to influence the parasite’s susceptibility to almost all of the current antimalarials.  Other determinants included the parasite’s Niemann-Pick type-C1 protein (PfNPC1) and the putative UDP-galactose:UMP antiporter (PfUGT).  A number of these 24 resistance-associated transporters are probably drug targets, others may reduce the access of drugs to their targets, whereas some – such as PfCRT and PfMDR1 – likely serve as both drug targets and drug transporters.  Alternatively, one or more of the transporters may fulfil compensatory roles.  We have been applying a set of complementary in vitro and in situ assays, including the Xenopus oocyte expression system, to elucidate the mechanisms by which polymorphisms in transporters alter the parasite’s sensitivity to drugs.  Key findings from this work will be presented.

  1. Martin et al (2005). Genome Biology, 6: R26.
  2. Martin, Ginsburg, and Kirk (2009). Molecular Microbiology, 74: 519-528.
  3. Cowell et al (2018). Science, 359: 191-199.