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Drug-induced quiescence may increase resistance in P. falciparum
Multidrug tolerance of Plasmodium falciparum to artemisinin derivatives occurs as a result of drug-induced dormancy, which facilitates the survival of parasites after exposure to unrelated antimalarial drugs, according to recent findings.
“Artemisinin resistance decreases parasite clearance rates and exposes larger numbers of parasites to antimalarial drugs in vivo, but whether it drives selection of higher-grade artemisinin resistance or resistance to the partner drug is unknown,” researchers from France wrote in Emerging Infectious Diseases.
To study the effect of extended artemisinin pressure on the susceptibility of P. falciparum to other antimalarial drugs, the researchers exposed the parasite to increasing doses of artemisinin over 5 years. They grew cultures of the F32-Tanzania clone, adjusted to a parasitemia of 5% to 7%, in the presence of increasing artemisinin pressure (range, 10 µmol/L to 9 µmol/L) for 24 hours for the first 3 years, yielding F32-ART3. During the next 2 years, the duration of each drug pressure cycle was 48 hours (range, 9 µmol/L–18 µmol/L), yielding F32-ART5. The researchers evaluated F32-ART5 parasites collected during the period extending from the 120th to the 123rd artemisinin pressure cycle. They cultivated F32-ART5 along with its sibling, the drug-sensitive F32-TEM, which was cultured without artemisinin. The researchers assessed the sensitivity of F32-ART5 and F32-TEM to 10 antimalarial drugs, and determined the 50% inhibitory concentrations (IC50s) after 48 hours of incubation. Synchronized F32-TEM and F32-ART5 ring stages were exposed to the drugs for 48 hours, and the researchers used a preliminary drug screening to determine the most suitable dose of antimalarial drug to differentiate the phenotype reaction of both lines in the recrudescence test. They monitored parasitemia daily to evaluate the time to recrudescence to the initial parasitemia.
Although IC50 levels for the evaluated antimalarial drugs did not change, the researchers found that drug-tolerant parasites had higher recrudescence rates for endoperoxides, quinolones and an antifolate, including partner drugs of recommended combination therapies. However, these parasites retained susceptibility to Mepron (atovaquone, GlaxoSmithKline).
Moreover, the age range of intraerythrocytic stages capable of resisting artemisinin was expanded to older ring forms and trophozoites.
The researchers noted that dormancy or stress-induced drug quiescence is a common characteristic of bacterial endurance against various antimicrobial drugs, with increased levels of enduring bacteria selected by periodic exposure to high levels of bactericidal agents.
“An analogous multidrug tolerance/resistance is induced in malaria parasites by extended exposure to high doses of artemisinin, which provides parasites with the capacity to survive lethal doses of diverse classes of antimalarial drugs, including molecules used as drug partners in currently recommended first-line combination therapies,” the researchers wrote. – by Jen Byrne
Disclosure: The researchers report no relevant financial disclosures.