A broad analysis of resistance development in the malaria parasite

Abstract

Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.

New developments in anti-malarial target candidate and product profiles

“…Recent studies with compounds from the open-access Malaria Box [41] have identified several chemotypes against which resistance cannot be generated in the laboratory [42]. Attractive scaffolds from within this set will be prioritized for optimization and progress, and in parallel, target identification will be important.…”

“…Other PfATP4 inhibitors are in development, with SJ733 (+−SJ00557733; [86, 87]) recently starting phase I studies. A concern with targeting PfATP4 is that mutations in this gene confer resistance against aminopyrazoles, dihydroisoquinolones and spiroindolones [42, 88, 89]. The developmental pathway could be to demonstrate safety and tolerability of a parenteral formulation whilst assessing activity in adults with moderately severe malaria (hyperparasitemic cases; [85]).…”

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

“…Longer-lasting drugs with similar modes of action might prove superior at reducing the risk of resistance. The rate of parasite killing is another important characteristic, with evidence showing that fast-acting antimalarials are less prone to yield resistance in vitro 131 . Resistance selection efforts have also proven unsuccessful with the potent antimalarial methylene blue that is active against the intra-erythrocytic asexual and gametocyte stages.…”

Directing Drug Evolution

“…From there, Winzelers group applied the strategy to look at a variety of gene mutations conferring resistance in the malaria parasite, Plasmodium (2). Over time, theyve even moved the strategy into looking at clinical trial candidates.…”