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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) ?5 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 ?5 inhibitors synergize with a ?2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA ?5 inhibitor surprisingly harbored a point mutation in the noncatalytic ?6 subunit. The ?6 mutant was resistant to the species-selective Pf20S ?5 inhibitor but remained sensitive to the species-nonselective ?5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S ?5 inhibitor was accompanied by increased sensitivity to a Pf20S ?2 inhibitor. Finally, the ?5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S ?5 and ?2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.

SUBMITTER: Kirkman LA

PROVIDER: S-EPMC6055138 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Kirkman Laura A LA Zhan Wenhu W Visone Joseph J Dziedziech Alexis A Singh Pradeep K PK Fan Hao H Tong Xinran X Bruzual Igor I Hara Ryoma R Kawasaki Masanori M Imaeda Toshihiro T Okamoto Rei R Sato Kenjiro K Michino Mayako M Alvaro Elena Fernandez EF Guiang Liselle F LF Sanz Laura L Mota Daniel J DJ Govindasamy Kavitha K Wang Rong R Ling Yan Y Tumwebaze Patrick K PK Sukenick George G Shi Lei L Vendome Jeremie J Bhanot Purnima P Rosenthal Philip J PJ Aso Kazuyoshi K Foley Michael A MA Cooper Roland A RA Kafsack Bjorn B Doggett J Stone JS Nathan Carl F CF Lin Gang G

Proceedings of the National Academy of Sciences of the United States of America 20180702 29

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the <i>Plasmodium falciparum</i> 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 <i>P. falciparum</i> strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and ...[more]

PMID: 29967165

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Project description:Mutations conferring resistance to one antibiotic can increase (cross-resistance) or decrease (collateral sensitivity) resistance to others. Antibiotic combinations displaying collateral sensitivity could be used in treatments that slow resistance evolution. However, lab-to-clinic translation requires understanding whether collateral effects are robust across different environmental conditions. Here, we isolated and characterized resistant mutants of Escherichia coli using five antibiotics, before measuring collateral effects on resistance to other paired antibiotics. During both isolation and phenotyping, we varied conditions in ways relevant in nature (pH, temperature, and bile). This revealed that local abiotic conditions modified expression of resistance against both the antibiotic used during isolation and other antibiotics. Consequently, local conditions influenced collateral sensitivity in two ways: by favoring different sets of mutants (with different collateral sensitivities) and by modifying expression of collateral effects for individual mutants. These results place collateral sensitivity in the context of environmental variation, with important implications for translation to real-world applications. IMPORTANCE When bacteria become resistant to an antibiotic, the genetic changes involved sometimes increase (cross-resistance) or decrease (collateral sensitivity) their resistance to other antibiotics. Antibiotic combinations showing repeatable collateral sensitivity could be used in treatment to slow resistance evolution. However, collateral sensitivity interactions may depend on the local environmental conditions that bacteria experience, potentially reducing repeatability and clinical application. Here, we show that variation in local conditions (pH, temperature, and bile salts) can influence collateral sensitivity in two ways: by favoring different sets of mutants during bacterial resistance evolution (with different collateral sensitivities to other antibiotics) and by modifying expression of collateral effects for individual mutants. This suggests that translation from the lab to the clinic of new approaches exploiting collateral sensitivity will be influenced by local abiotic conditions.

Dataset Information

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

Publications

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

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