Mechanisms of resistance to the partner drugs of artemisinin in the malaria parasite

The transportome of the malaria parasite

“…Overall, a staggering 53% of the resistance determinants identified within the study were transporters (yet transporter genes make up only 2.5% of the parasite's genome). These genes included established resistance determinants such as PfCRT and PfMDR1, which were originally identified for their roles in conferring chloroquine resistance (Foote et al ., ; Fidock et al ., ), but are now known to influence the parasite's susceptibility to many of the current antimalarials (reviewed by (Martin et al ., ). Others have recently emerged as determinants of resistance to drugs in the development pipeline or in clinical trial (e.g.…”

“…PfCRT, PfMDR1, and PfUGT) impart significant fitness costs to the parasite (Rosenthal, ; Lim et al ., ) to the extent that for PfCRT and PfMDR1, the withdrawal of the relevant antimalarial from a malarious region tends to result in the re‐emergence of parasites carrying the wild‐type allele (reviewed by Rosenthal, ) or the emergence of additional polymorphisms in the mutant allele that re‐sensitise the parasite to the drug and for which the main purpose may be to reinstate fitness (Summers et al ., ; Pelleau et al ., ). The propensity of the essential transporters to be subject to conflicting selection forces could be exploited to delay or combat resistance through the rational design of drug combinations (Yuan et al ., ; Summers et al ., ; Lukens et al ., ; Richards et al ., ; Martin et al ., ).…”

“…There are a number of ways by which a polymorphism in a transporter gene could confer, or contribute to, drug resistance (reviewed by Summers, Nash & Martin, 2012;Martin et al, 2018). For example, it could bring about a reduction in the concentration of the drug at its site of action by causing the transporter to gain (or lose) the ability to transport the drug.…”

“…These combinations bring together the rapid parasiticidal action (but short half‐life) of dihydroartemisinin with the slower action (but longer half‐life) of the partner drug. Whilst initially very effective in reducing the malaria burden, parasites resistant to one or more of the current partner drugs, and/or which are partly resistant to dihydroartemisinin, have emerged and are spreading (reviewed by Woodrow & White, and Martin, Shafik & Richards, ).…”

“…These combinations bring together the rapid parasiticidal action (but short half-life) of dihydroartemisinin with the slower action (but longer half-life) of the partner drug. Whilst initially very effective in reducing the malaria burden, parasites resistant to one or more of the current partner drugs, and/or which are partly resistant to dihydroartemisinin, have emerged and are spreading (reviewed by White, 2017 andRichards, 2018). The capacity of the parasite to continue to evolve resistance to diverse drugs necessitates the identification of new drug targets, a detailed understanding of the determinants of drug resistance and the mechanisms by which they alter drug susceptibility, and a greater knowledge of the parasite's cell physiology.…”