Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance Journal Article
| Authors: | Kirkman, L. A.; Zhan, W.; Visone, J.; Dziedziech, A.; Singh, P. K.; Fan, H.; Tong, X.; Bruzual, I.; Hara, R.; Kawasaki, M.; Imaeda, T.; Okamoto, R.; Sato, K.; Michino, M.; Fernandez Alvaro, E.; Guiang, L. F.; Sanz, L.; Mota, D. J.; Govindasamy, K.; Wang, R.; Ling, Y.; Tumwebaze, P. K.; Sukenick, G.; Shi, L.; Vendome, J.; Bhanot, P.; Rosenthal, P. J.; Aso, K.; Foley, M. A.; Cooper, R. A.; Kafsack, B.; Stone Doggett, J.; Nathan, C. F.; Lin, G. |
| Article Title: | Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance |
| Abstract: | We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other. © 2018 National Academy of Sciences. All rights reserved. |
| Keywords: | malaria; plasmodium; proteasome inhibitors; artemisinin; collateral sensitivity |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 115 |
| Issue: | 29 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2018-07-17 |
| Start Page: | E6863 |
| End Page: | E6870 |
| Language: | English |
| DOI: | 10.1073/pnas.1806109115 |
| PROVIDER: | scopus |
| PMCID: | PMC6055138 |
| PUBMED: | 29967165 |
| DOI/URL: | |
| Notes: | Review -- Export Date: 1 August 2018 -- Source: Scopus |
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