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

Laura A Kirkman; Wenhu Zhan; Joseph Visone; Alexis Dziedziech; Pradeep K Singh; Hao Fan; Xinran Tong; Igor Bruzual; Ryoma Hara; Masanori Kawasaki; Toshihiro Imaeda; Rei Okamoto; Kenjiro Sato; Mayako Michino; Elena Fernandez Alvaro; Liselle F Guiang; Laura Sanz; Daniel J Mota; Kavitha Govindasamy; Rong Wang; Yan Ling; Patrick K Tumwebaze; George Sukenick; Lei Shi; Jeremie Vendome; Purnima Bhanot; Philip J Rosenthal; Kazuyoshi Aso; Michael A Foley; Roland A Cooper; Bjorn Kafsack; J Stone Doggett; Carl F Nathan; Gang Lin

doi:10.1073/pnas.1806109115

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

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

Laura A Kirkman, Wenhu Zhan, Joseph Visone, Alexis Dziedziech, Pradeep K Singh, Hao Fan, Xinran Tong, Igor Bruzual, Ryoma Hara, Masanori Kawasaki, …

Proceedings of the National Academy of Sciences - PNAS, Vol.115(29), pp.E6863-E6870

07/17/2018

DOI: https://doi.org/10.1073/pnas.1806109115

PMCID: PMC6055138

PMID: 29967165

Abstract

Antimalarials - chemistry

Artemisinins - chemistry

Bortezomib - chemistry

Drug Resistance, Microbial

Humans

Lactones - chemistry

Oligopeptides - chemistry

Plasmodium falciparum - enzymology

Proteasome Endopeptidase Complex - chemistry

Proteasome Inhibitors - chemistry

Protozoan Proteins - antagonists & inhibitors

Protozoan Proteins - chemistry

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.

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Title: Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance
Creators: Laura A Kirkman - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065
Wenhu Zhan - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065
Joseph Visone - Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, NY 10065
Alexis Dziedziech - Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, NY 10065
Pradeep K Singh - Chemical Core Facility, Department of Biochemistry, Weill Cornell Medicine, NY 10065
Hao Fan - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065
Xinran Tong - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065
Igor Bruzual - Department of Research and Development, Portland Veterans Affairs Medical Center, Oregon Health and Science University, Portland, OR 97239
Ryoma Hara - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Masanori Kawasaki - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Toshihiro Imaeda - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Rei Okamoto - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Kenjiro Sato - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Mayako Michino - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Elena Fernandez Alvaro - Diseases of the Developing World (DDW), Tres Cantos Medicine Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain
Liselle F Guiang - Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA 94901
Laura Sanz - Diseases of the Developing World (DDW), Tres Cantos Medicine Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain
Daniel J Mota - Department of Medicine, University of California, San Francisco, CA 94143
Kavitha Govindasamy - Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 11201
Rong Wang - NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065
Yan Ling - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065
Patrick K Tumwebaze - Infectious Diseases Research Collaboration, Kampala, Uganda
George Sukenick - NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065
Lei Shi - Department of Biophysics, Weill Cornell Medicine, NY 10065
Jeremie Vendome - Schrödinger, Inc., New York, NY 10036
Purnima Bhanot - Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 11201
Philip J Rosenthal - Department of Medicine, University of California, San Francisco, CA 94143
Kazuyoshi Aso - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Michael A Foley - Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065
Roland A Cooper - Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA 94901
Bjorn Kafsack - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065
J Stone Doggett - Department of Research and Development, Portland Veterans Affairs Medical Center, Oregon Health and Science University, Portland, OR 97239
Carl F Nathan - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065; lak9015@med.cornell.edu cnathan@med.cornell.edu gal2005@med.cornell.edu
Gang Lin - Department of Microbiology and Immunology, Weill Cornell Medicine, NY 10065; lak9015@med.cornell.edu cnathan@med.cornell.edu gal2005@med.cornell.edu
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.115(29), pp.E6863-E6870
Date published: 07/17/2018
Grant note: R01 AI075045 / NIAID NIH HHS R21 AI094167 / NIAID NIH HHS R56 AI075045 / NIAID NIH HHS R21 AI101393 / NIAID NIH HHS R21 AI123794 / NIAID NIH HHS TL4 GM118986 / NIGMS NIH HHS IK2 BX002440 / BLRD VA P30 CA008748 / NCI NIH HHS
Academic Unit: Biology (FASC); Microbiology, Biochemistry and Molecular Genetics (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031665717104646