Microbiology and Immunology

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Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

TitleAntimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.
Publication TypeJournal Article
Year of Publication2018
AuthorsKirkman LA, Zhan W, Visone J, Dziedziech A, Singh PK, Fan H, Tong X, Bruzual I, Hara R, Kawasaki M, Imaeda T, Okamoto R, Sato K, Michino M, Alvaro EFernandez, Guiang LF, Sanz L, Mota DJ, Govindasamy K, Wang R, Ling Y, Tumwebaze PK, Sukenick G, Shi L, Vendome J, Bhanot P, Rosenthal PJ, Aso K, Foley MA, Cooper RA, Kafsack B, J Doggett S, Nathan CF, Lin G
JournalProc Natl Acad Sci U S A
Volume115
Issue29
PaginationE6863-E6870
Date Published2018 07 17
ISSN1091-6490
KeywordsAntimalarials, Artemisinins, Bortezomib, Drug Resistance, Microbial, Humans, Lactones, Oligopeptides, Plasmodium falciparum, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protozoan Proteins
Abstract

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the 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 strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. 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.

DOI10.1073/pnas.1806109115
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29967165
PubMed Central IDPMC6055138
Grant ListR21 AI094167 / AI / NIAID NIH HHS / United States
R21 AI101393 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R21 AI123794 / AI / NIAID NIH HHS / United States
R01 AI075045 / AI / NIAID NIH HHS / United States
R56 AI075045 / AI / NIAID NIH HHS / United States
IK2 BX002440 / BX / BLRD VA / United States

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