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.
[doi:10.25345/C5T50P]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: Metabolomics
Principal Investigators: (in alphabetical order) |
Heather Painter, U.S. Food & Drug Administration, United States |
Submitting User: | mwang87 |
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