Combining Stage Specificity and Metabolomic Profiling to Advance Antimalarial Drug Discovery

Abstract

Highlights d Timing of peak activity during life cycle informs on mode of action of antimalarials d Results differentiated modes of action of piperaquine, lumefantrine, and atovaquone d Experimental compounds targeted previously unexplored druggable pathways d Characterized ring-active compounds and new heme or mitochondrial inhibitors

Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity

“…MMV030084 induced only minor changes within the set of detected metabolites in both stages ( Table S1 (C)). This metabolic profile was distinct from inhibitors known to affect targets such as hemoglobin catabolism, the mitochondrial electron transport chain, pyrimidine biosynthesis, or cellular homeostasis ( Murithi et al., 2019 ).…”

“…Unsynchronized parasites were exposed for 72 h to 10 different concentrations of MMV030084 or its analogs, plus control no-drug conditions, starting with predominantly rings ( Murithi et al., 2019 ). We also exposed specific stages of highly-synchronized parasites to MMV030084 to determine the period of peak activity, defined as the asexual blood stage at which the compounds showed the lowest IC 50 8h values ( Murithi et al., 2019 ). Synchronicity was achieved using three rounds of sorbitol treatment on early rings, spaced 48 h apart, followed by magnetic purification of segmented schizonts following the final sorbitol treatment.…”

Rapid and quantitative antimalarial drug efficacy testing via the magneto-optical detection of hemozoin

“…3c and Supplementary Table S1.) [27][28][29][30][31][32][33] . The average IC50 value determined from the assays at 0.1% parasitemia (IC50 = 30.61 ± 4.01 nM) is significantly lower compared to that obtained for 1% parasitemia (Fig.…”

Glutamine metabolism modulates azole susceptibility inTrypanosoma cruziamastigotes

“…Similarly, standard in vitro inhibitory activity of a candidate compound can be confounded by altered pathogen metabolism due to growth media composition (Hicks et al, 2018; Pethe et al, 2010) and conversely an understanding of these interactions can potentiate treatment (Vestergaard et al, 2017). These complex interactions are best understood in cases of bacterial pathogenesis, but recently, similar trends are apparent in eukaryotic pathogens (Dumont et al, 2019; McLean and Jacobs-Lorena, 2017; Murithi et al, 2020).…”