Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility.

Abstract

Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deleting the homologous gene in P. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.

• Authors: Clare R Harding, Saima M Sidik, Boryana Petrova, Nina F Gnädig, John Okombo, Alice L Herneisen, Kurt E Ward, Benedikt M Markus, Elizabeth A Boydston, David A Fidock, Sebastian Lourido
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4813 (09 23 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32968076 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antimalarials
• Artemisinins
• Membrane Transport Proteins
• Protozoan Proteins
• Heme
• artenimol
• artemisinin

Topics

• Antimalarials (pharmacology)
• Artemisinins (pharmacology)
• Clustered Regularly Interspaced Short Palindromic Repeats
• Drug Resistance (genetics)
• Gene Knockout Techniques
• Genetic Testing (methods)
• Heme (genetics, metabolism)
• Humans
• Malaria, Falciparum (drug therapy)
• Membrane Transport Proteins (metabolism)
• Mutation
• Plasmodium falciparum (drug effects, genetics)
• Protozoan Proteins (genetics)
• Toxoplasma (drug effects, genetics)