Selection of Plasmodium falciparum cytochrome B mutants by putative PfNDH2 inhibitors

Proceedings of the National Academy of Sciences of the United States of America
Kristin D LaneT E Wellems

Abstract

Malaria control is threatened by a limited pipeline of effective pharmaceuticals against drug-resistant strains of Plasmodium falciparum Components of the mitochondrial electron transport chain (ETC) are attractive targets for drug development, owing to exploitable differences between the parasite and human ETC. Disruption of ETC function interferes with metabolic processes including de novo pyrimidine synthesis, essential for nucleic acid replication. We investigated the effects of ETC inhibitor selection on two distinct P. falciparum clones, Dd2 and 106/1. Compounds CK-2-68 and RYL-552, substituted quinolones reported to block P. falciparum NADH dehydrogenase 2 (PfNDH2; a type II NADH:quinone oxidoreductase), unexpectedly selected mutations at the quinol oxidation (Qo) pocket of P. falciparum cytochrome B (PfCytB). Selection experiments with atovaquone (ATQ) on 106/1 parasites yielded highly resistant PfCytB Y268S mutants seen in clinical infections that fail ATQ-proguanil treatment. In contrast, ATQ pressure on Dd2 yielded moderately resistant parasites carrying a PfCytB M133I or K272R mutation. Strikingly, all ATQ-selected mutants demonstrated little change or slight increase of sensitivity to CK-2-68 or RYL-552. Molecular ...Continue Reading

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Citations

Jun 24, 2020·FEBS Letters·Nicholas FisherGiancarlo A Biagini
Oct 21, 2020·Antimicrobial Agents and Chemotherapy·T Parks RemchoKristin D Lane
Oct 15, 2020·Molecular Microbiology·Jennifer M McDanielsJennifer L Guler
Apr 14, 2021·Chemistry : a European Journal·Quentin RonzonBastien Nay
Nov 17, 2020·International Journal for Parasitology. Drugs and Drug Resistance·Sean T WindleThomas E Wellems
Mar 12, 2019·Journal of Medicinal Chemistry·Rozalia A DodeanJane X Kelly

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