Figure 5
Effects of pyrazoleamide treatment in P. falciparum. Our integrated model analysis suggests that a sublethal dose of pyrazoleamide (PYZ) caused a reduction in PfATP4 flux, disrupting the homeostasis of sodium ions (Na+) and protons (H+) and, ultimately, reducing the osmotic pressure. The model also indicated reduced uptake of amino acids (AA), such as isoleucine, and a decreased rate of protein synthesis in drug-treated parasites. We found that the parasites adjust carbohydrate metabolism to produce an osmolyte (MI) that can counter the effects of drug treatment. However, this metabolic adjustment results in decreased flux via PPP, consequently decreasing NADPH and PRPP, and exacerbating the effects of the drug by increasing oxidative stress. Hence, our results suggest that downstream consequences of metabolic adjustments contribute to the efficacy of pyrazoleamides in P. falciparum. AA amino acid, ADP adenosine diphosphate, ATP adenosine triphosphate, G6P glucose 6-phosphate, GLC D-glucose, Hb hemoglobin, MI myoinositol, NADPH nicotinamide adenine dinucleotide phosphate, Pi inorganic phosphate, PPP pentose phosphate pathway, PRPP 5-phosphoribosyl 1-pyrophosphate, tRNA transfer RNA.
