Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.

Gregory M LaMonte, Elizabeth A Winzeler, Yo Suzuki, Rommie E Amaro, Carolyn W Slayman, Case W McNamara, Maximo Prescott, Rebecca Murray, Marie Nachon, Ayako Murao, Micah J Manary, Gregory M Goldgof, Jake Schenken, Jennifer Yang, Kiersten A Henderson, Maxim Kostylev, Felicia Gunawan, Kenneth E Allen, Edgar Vigil, Sabine Ottilie, Jacob D Durrant

Journal: Scientific reports 2018;6():27806

PMID: 27291296

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Abstract

The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.

Address: Division of Pharmacology and Drug Discovery, Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, California, USA.; Department of Synthetic Biology and Bioenergy, J. Craig Venter Institute, La Jolla, California, USA.; Department of Chemistry &Biochemistry and the National Biomedical Computation Resource, University of California, San Diego, La Jolla, California, USA.; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.

DOI: 10.1038/srep27806

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MeSH Terms: Amino Acid Sequence, Antimalarials, Binding Sites, CRISPR-Cas Systems, Cytosol, Drug Resistance, Fungal, Indoles, Inhibitory Concentration 50, Molecular Docking Simulation, P-type ATPases, Plasmodium falciparum, Protein Structure, Tertiary, Proton-Translocating ATPases, Protozoan Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Alignment, Sequence Analysis, DNA, Spiro Compounds, Structure-Activity Relationship, Whole Genome Sequencing