The Biochemistry of Quinoline Antimalarial Drug Resistance

Abstract

Mutations in the Plasmodium falciparum chloroquine-resistance transporter (PfCRT) have been shown to be central to the molecular mechanism of quinoline antimalarial drug resistance. However, additional facets to resistance biochemistry are emerging, and it is now clear that multiple quinoline drug resistance phenotypes exist in different regions of the globe. Different public health policies and drug use histories across the globe, along with natural genetic drift, have created this diversity, such that there are now dozens of distinct chloroquine-resistant (CQR) strains of P. falciparum. Some of these can be described in detail, but information is incomplete. This leads to some degree of continued uncertainty on how best to proceed in controlling malaria in some regions. This issue is even more critical for controlling chloroquine-resistant P. vivax, about which even less is known. This review summarizes key features of quinoline antimalarial drug resistance in P. falciparum malaria and suggests concepts relevant for "staying ahead of the resistance curve."

Mode of action of quinoline antimalarial drugs in red blood cells infected by Plasmodium falciparum revealed in vivo

“…S6). We interpret this observation as either lack of resistance to BrQ by the FCR3 strain or a resistance mechanism other than the previously suggested reduction of BrQ concentration in the digestive vacuole (1). Further investigation needs to be conducted to clarify this point.…”

“…Our focus will be on the most virulent of such species, Plasmodium falciparum . Increasing geographical spread of the species resistant to current drug treatments is a cause of serious concern (1–3). Characterizing how current antimalarial drugs work at the molecular level is a key for intelligent design of improved antimalarial drugs needed to combat the disease.…”