Files and links (1)
Published, Version of Record (VoR)CC BY V4.0, Open
Journal article
Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages
PloS one, v 14(4), pp e0214023-e0214023
2019
PMID: 30964863
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The battle against malaria has been substantially impeded by the recurrence of drug resistance in Plasmodium falciparum, the deadliest human malaria parasite. To counter the problem, novel antimalarial drugs are urgently needed, especially those that target unique pathways of the parasite, since they are less likely to have side effects. The mitochondrial type II NADH dehydrogenase (NDH2) of P. falciparum, PfNDH2 (PF3D7_0915000), has been considered a good prospective antimalarial drug target for over a decade, since malaria parasites lack the conventional multi-subunit NADH dehydrogenase, or Complex I, present in the mammalian mitochondrial electron transport chain (mtETC). Instead, Plasmodium parasites contain a single subunit NDH2, which lacks proton pumping activity and is absent in humans. A significant amount of effort has been expended to develop PfNDH2 specific inhibitors, yet the essentiality of PfNDH2 has not been convincingly verified. Herein, we knocked out PfNDH2 in P. falciparum via a CRISPR/Cas9 mediated approach. Deletion of PfNDH2 does not alter the parasite's susceptibility to multiple mtETC inhibitors, including atovaquone and ELQ-300. We also show that the antimalarial activity of the fungal NDH2 inhibitor HDQ and its new derivative CK-2-68 is due to inhibition of the parasite cytochrome bc1 complex rather than PfNDH2. These compounds directly inhibit the ubiquinol-cytochrome c reductase activity of the malarial bc1 complex. Our results suggest that PfNDH2 is not likely a good antimalarial drug target.
Metrics
12 Record Views
Details
- Title
- Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages
- Creators
- Hangjun Ke - Drexel UniversitySuresh M Ganesan - Drexel UniversitySwati Dass - Drexel UniversityJoanne M Morrisey - Drexel UniversitySovitj Pou - Portland VA Medical CenterAaron Nilsen - Portland VA Medical CenterMichael K Riscoe - Portland VA Medical CenterMichael W Mather - Drexel UniversityAkhil B Vaidya - Drexel University
- Publication Details
- PloS one, v 14(4), pp e0214023-e0214023
- Publisher
- Public LIbrary of Science (PLOS)
- Grant note
- R01 AI100569 / NIAID NIH HHS K22 AI127702 / NIAID NIH HHS R01 AI028398 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000463876300011
- Scopus ID
- 2-s2.0-85064078091
- Other Identifier
- 991019168986304721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology