Defining the timing of action of antimalarial drugs against Plasmodium falciparum
Language: 
English
Abstract: 

Most current antimalarials for treatment of clinical Plasmodium falciparum malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion in vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for in vitro assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials.

Author(s): 
Wilson, Danny W.
Langer, Christine
Goodman, Christopher D.
McFadden, Geoffrey I.
Beeson, James G.
Item Type: 
Journal Article
Publication Title: 
Antimicrobial Agents and Chemotherapy
Journal Abbreviation: 
Antimicrob. Agents Chemother.
Publication Date: 
3/13/2015
Publication Year: 
2013
Pages: 
1455-1467
Volume: 
57
Issue: 
3
ISSN: 
1098-6596
DOI: 
10.1128/AAC.01881-12
Library Catalog: 
PubMed
Extra: 
PMID: 23318799 PMCID: PMC3591904

Turabian/Chicago Citation

Danny W. Wilson, Christine Langer, Christopher D. Goodman, Geoffrey I. McFadden and James G. Beeson. 3/13/2015. "Defining the timing of action of antimalarial drugs against Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 57: 3: 1455-1467. 10.1128/AAC.01881-12.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1128/AAC.01881-12 | issn = 1098-6596 | volume = 57 | pages = 1455-1467 | last = Wilson | first = Danny W. | coauthors = Langer, Christine, Goodman, Christopher D., McFadden, Geoffrey I., Beeson, James G. | title = Defining the timing of action of antimalarial drugs against Plasmodium falciparum | journal = Antimicrobial Agents and Chemotherapy | date = 3/13/2015 | pmid = | pmc = }} </ref>