In vitro selection of Plasmodium falciparum drug-resistant parasite lines

Abstract

The in vitro selection of antimicrobial resistance in important pathogens can provide critical information on the genetic basis of drug resistance, and such information can be used to predict, anticipate and even contain the spread of resistance in clinical practice. For instance, the discovery of the role of pfmdr1 in mefloquine resistance in malaria parasites resulted from in vitro studies. However, the in vitro selection of resistance is difficult, challenging and time consuming. In this review, we discuss the key parameters that impact on the efficiency of the in vitro selection of resistance, and propose strategies to improve and streamline this process.

Figure 1

Drug–response as a function of the concentration. Any right shift of the curve denotes an increase in the IC₅₀ and, thus, the resistance. The shift can be parallel or the shape of the curve and the maximum effect (E_max) could change. Reproduced from Trends in Parasitology, 18(10), White NJ, The assessment of antimalarial drug efficacy, 458–64, 2002, with permission from Elsevier.

Figure 2

Dose concentration–response of an in vitro-selected mefloquine (MFQ)-resistant line that could grow in the presence of >1200 ng/mL mefloquine. The dose–response was analysed using a modification of the logistic logarithmic function that permits evaluation of a biphasic concentration–response relationship. Two parasite populations with different IC₅₀s can be defined from this graph, yet the use of a monophasic concentration–response would have generated one single IC₅₀ (inhibitory concentration that kills 50% of parasites). Reproduced, with permission, from Peel et al. (Figure 4b).