Plasmodium falciparum field isolates drug susceptibility in Mali

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 To assess the ex vivo susceptibility of P. falciparum field isolates to 14 antimalarials, including withdrawn/unused and currently used drugs, and next-generation agents in Mali.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.