Malaria drug resistance: new observations and developments

Abstract

Drug-resistant micro-organisms became widespread in the 20th Century, often with devastating consequences, in response to widespread use of natural and synthetic drugs against infectious diseases. Antimalarial resistance provides one of the earliest examples, following the introduction of new medicines that filled important needs for prophylaxis and treatment around the globe. In the present chapter, we offer a brief synopsis of major antimalarial developments from two natural remedies, the qinghaosu and cinchona bark infusions, and of synthetic drugs inspired by the active components of these remedies. We review some contributions that early efficacy studies of antimalarial treatment brought to clinical pharmacology, including convincing documentation of atebrine-resistant malaria in the 1940s, prior to the launching of what soon became first-choice antimalarials, chloroquine and amodiaquine. Finally, we discuss some new observations on the molecular genetics of drug resistance, including delayed parasite clearances that have been increasingly observed in response to artemisinin derivatives in regions of South-East Asia.

Figure 1. Chemical structures of antimalarial drugs inspired by the active compounds of cinchona bark and qinghao

Antimalarials inspired by the active compounds of the cinchona bark are characterized by the presence of a quinoline heteroaromatic nucleus. Represented quinoline antimalarials include: QN, a quinoline methanol; the 8-aminoquinolines pamaquine and PQ; the acridine-based compounds ATB and pyronaridine; and the 4-aminoquinolines CQ, AQ, its active metabolite MDAQ, and the bisquinoline piperaquine. It is suggested that the target of most quinoline antimalarials is haematin (aquaferriprotoporphyrin IX), an autoxidized haem released during haemoglobin degradation and found as crystallized dimers in the acidic vacuoles of infected red blood cells of Plasmodium parasites. Most quinoline drugs complex with haematin, which is thought to kill the parasite by an oxidative or osmotic mechanism. Antimalarials inspired by the active compounds of qinghao include the sesquiterpene lactone ART, and its derivatives dihydroartemisinin, artesunate and artemether. The endoperoxide bridge is crucial for its antiparasitic activity and is proposed to cause oxidative stress by the formation of ROS. A recent fully synthetic endoperoxide antimalarial inspired by ART is arterolane (OZ277), which presents a spiroadamantane trixoloane pharmacophore and neutral or basic functional groups designed to improve oral bioavailability and increase its half-life.

Figure 2. Predicted protein structure of PfCRT and geographic distribution of major haplotypes based on codon positions 72–76

(A) Schematic representation of predicted PfCRT structure with ten transmembrane domains and the amino acid positions that have been found to carry mutations in P. falciparum field isolates (black dots). Mutations at positions 163 and 352 that have been selected only in laboratory experiments are not shown [112,113]. Major reported amino acid substitutions at codon positions 72, 74, 75 and 76 are indicated in single letter amino acid code. Reprinted from Current Opinion in Microbiology, vol. 4, Carlton, J.M., Fidock, D.A., Djimde, A., Plowe, C.V. and Wellems, T.E., Conservation of a novel vacuolar transporter in Plasmodium species and its central role in chloroquine resistance of P. falciparum, pp. 415–420, © 2001, with permission from Elsevier. (B) Distribution of reported PfCRT haplotypes (observed in more than a single isolate) from malaria endemic regions. Reprinted with permission from Proceedings of the National Academy of Sciences U.S.A., vol. 106, Sa, J.M., Twu, O., Hayton, K., Reyes, S., Fay, M.P., Ringwald, P. and Wellems, T.E., Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine, pp. 18883–18889, © 2009, National Academy of Sciences, and updated from data in [,–119]. CQS, CQ sensitivity.