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Journal article
Atypical Molecular Basis for Drug Resistance to Mitochondrial Function Inhibitors in Plasmodium falciparum
Antimicrobial agents and chemotherapy, v 65(3)
17 Feb 2021
PMID: 33361312
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The continued emergence of drug-resistant Plasmodium falciparum parasites hinders global attempts to eradicate malaria, emphasizing the need to identify new antimalarial drugs. Attractive targets for chemotherapeutic intervention are the cytochrome (cyt) bc1 complex, which is an essential component of the mitochondrial electron transport chain (mtETC) required for ubiquinone recycling and mitochondrially localized dihydroorotate dehydrogenase (DHODH) critical for de novo pyrimidine synthesis. Despite the essentiality of this complex, resistance to a novel acridone class of compounds targeting cyt bc1 was readily attained, resulting in a parasite strain (SB1-A6) that was panresistant to both mtETC and DHODH inhibitors. Here, we describe the molecular mechanism behind the resistance of the SB1-A6 parasite line, which lacks the common cyt bc1 point mutations characteristic of resistance to mtETC inhibitors. Using Illumina whole-genome sequencing, we have identified both a copy number variation (∼2×) and a single-nucleotide polymorphism (C276F) associated with pfdhodh in SB1-A6. We have characterized the role of both genetic lesions by mimicking the copy number variation via episomal expression of pfdhodh and introducing the identified single nucleotide polymorphism (SNP) using CRISPR-Cas9 and assessed their contributions to drug resistance. Although both of these genetic polymorphisms have been previously identified as contributing to both DSM-1 and atovaquone resistance, SB1-A6 represents a unique genotype in which both alterations are present in a single line, suggesting that the combination contributes to the panresistant phenotype. This novel mechanism of resistance to mtETC inhibition has critical implications for the development of future drugs targeting the bc1 complex or de novo pyrimidine synthesis that could help guide future antimalarial combination therapies and reduce the rapid development of drug resistance in the field.
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Details
- Title
- Atypical Molecular Basis for Drug Resistance to Mitochondrial Function Inhibitors in Plasmodium falciparum
- Creators
- Heather J Painter - Pennsylvania State UniversityJoanne M Morrisey - Drexel UniversityMichael W Mather - Drexel UniversityLindsey M Orchard - Pennsylvania State UniversityCuyler Luck - Pennsylvania State UniversityMartin J Smilkstein - Medical Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon, USAMichael K Riscoe - Medical Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon, USAAkhil B Vaidya - Drexel UniversityManuel Llinás - Pennsylvania State University
- Publication Details
- Antimicrobial agents and chemotherapy, v 65(3)
- Publisher
- American Society for Microbiology
- Number of pages
- 13
- Grant note
- OPP1119049 / Bill and Melinda Gates Foundation (BMGF) (https://doi.org/10.13039/100000865) R01 AI028398 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) 14S-RCS001 / Veterans Administration Research Career Scientist Award HHS | U.S. Food and Drug Administration (FDA) (https://doi.org/10.13039/100000038) AI100569 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) P50 GM071508 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) 1DP2OD001315-01 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000619864100043
- Scopus ID
- 2-s2.0-85101740855
- Other Identifier
- 991019169806804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy