K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates

Abstract

The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.

Pfmdr1 gene polymorphism of Plasmodium falciparum isolates from asymptomatic individuals of Dienga, southeastern Gabon

“…Moreover, this resistance was firmly established in Cambodia, Thailand, Vietnam and Burma and its possible spread over the rest of South-east Asia has been documented [12,13]. On the other hand, the therapeutic failures of ACTs could be associated with single nucleotide polymorphism (SNP) in P. falciparum multidrug resistance gene-1 (Pfmdr1) [14,13], as well as with K13 propeller [15,16]. Pfmdr1 is an ATP cassette protein located on the parasite's food vacuole.…”

Biology of Malaria Transmission

“…To block transmission, ACT is often combined with the only transmissionblocking drug on the market, Primaquine. However, recent emergence of artemisinin resistance in Southeast Asia asks for urgent evaluation of alternative treatment strategies (Noedl et al 2008;Dondorp et al 2009;Mbengue et al 2015;Straimer et al 2015).Of the five Plasmodium species known to cause malaria in humans, Plasmodium falciparum is lethal and responsible for severe disease pathology and the majority of deaths due to malaria, especially in sub-Saharan Africa. Plasmodium vivax typically causes milder infections than P. falciparum but has a much greater geographical distribution (Gething et al 2012).…”

Drug Resistance in Malaria-in a nutshell

“…The C580Y mutation reduces polyubiquitination of P. falciparum phosphatidylinositol-3-kinase (PfPI3K), which in turn limits the proteolysis of PfPI3K leading to an increase in its level along with the level of its lipid product phosphatidylinositol-3-phosphate (PI3P). Thus along with the K13 mutation marker, PI3Plevels can also be predictive of artemisinin resistance (Ghorbal et al, 2014;Straimer et al, 2015;Mok et al, 2015;Ariey et al, 2014). Despite their rapid activity and high potency, even in the face of multi-drug resistant malarial parasites, the artemisininsare not used as a monotherapy due to their limited ability to eradicate the infection into to.…”