Plasmodium falciparum field isolates drug susceptibility in Mali

TL;DR

This study tests malaria parasite drug susceptibility in Mali, finding that current treatments remain effective but next-generation drugs show promise.

Contribution

The study provides new ex vivo drug susceptibility data for Plasmodium falciparum isolates in Mali, including next-generation antimalarials.

Findings

Current frontline drugs like dihydroartemisinin and lumefantrine remain highly potent against P. falciparum isolates.

Next-generation compounds cabamiquine and GNF179 show consistently strong activity with low IC50 values.

Reduced activity of chemopreventive drugs like sulfadoxine and pyrimethamine suggests the need for continued surveillance.

Abstract

The emergence and spread of antimalarial drug resistance threaten malaria control efforts in sub-Saharan Africa. Monitoring the susceptibility of circulating Plasmodium falciparum isolates is essential to inform national treatment guidelines and guide the development of new therapies. To assess the ex vivo susceptibility of P. falciparum field isolates to 14 antimalarials, including withdrawn/unused and currently used drugs, and next-generation agents in Mali.

Twenty-six isolates collected from patients with uncomplicated malaria at three endemic sites (Faladje, Kolle and Bougoula-Hameau) were cultured ex vivo under standardized conditions. Parasites were exposed to 14 drugs, including tafenoquine, N-desethyl-amodiaquine, chloroquine, dihydroartemisinin, lumefantrine, pyronaridine, quinine, sulfadoxine, pyrimethamine, amodiaquine, atovaquone, GNF179, KDU691 and cabamiquine. Susceptibility was measured using fluorescence-based assays with SYBR Green I and Mitotracker dyes, and IC50 values were derived from dose–response curves.

Tafenoquine showed a very low potency (IC50 > 1500 nM). Chloroquine exhibited marked inter- and intra-site variability (IC50 ∼50–1300 nM), while N-desethyl-amodiaquine potently inhibited isolates (median IC50 < 20 nM in Faladje and Bougoula-Hameau). Current frontline drugs, dihydroartemisinin (median IC50 < 6 nM), lumefantrine (median IC50 < 50 nM) and pyronaridine (median IC50 < 10 nM), remained highly potent. Quinine showed variable efficacy (IC50 ∼75–1000 nM). Chemoprevention agents sulfadoxine and pyrimethamine displayed high IC50 values (median IC50 > 1000 and >2000 nM). Atovaquone and amodiaquine consistently inhibited all isolates (IC50 < 10 nM). Next-generation compounds cabamiquine and GNF179 demonstrated consistently strong activity (IC50 < 10 nM), while KDU691 showed moderate activity (median IC50 18–22 nM).

While current frontline therapies remain effective, reduced activity of chemopreventive antimalarials supports the need for continued surveillance to detect early signs of resistance in Mali. The potent activity of next-generation candidates (cabamiquine and GNF179) supports their potential for further clinical development and field deployment.

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