GNPS Metabolomics Workbench ST001652 - GNPS Atypical Molecular Basis for Drug Resistance to Mitochondrial AQ: A Function Inhibitors in Plasmodium falciparum

In this study, we present a clear genotype for the P. falciparum SB1-A6 acridone-resistant clonal parasite strain and, through a combination of targeted and whole-cell methods, establish that the mechanism of resistance to both cytochrome bc1 and DHODH inhibitors results from the contribution of multiple genetic polymorphisms. We find that P. falciparum SB1-A6 accumulates both a copy number variation and a specific mutation in PfDHODH, and both of these genetic polymorphisms contribute to the panresistant phenotype. This study uncovers a mechanism of cross-resistance between PfDHODH and mtETC inhibitors and serves as a cautionary note to future antimalarial combination therapy formulations containing such drugs.