Fungal-derived methyldeoxaphomins target <i>Plasmodium falciparum</i> segregation through the inhibition of PfActin1
Abstract
Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus Trichocladium asperum that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in Plasmodium falciparum with the most potent member, NPDG-F (EC 50 of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure–activity relationships for the methyldeoxaphomin family. When added to in vitro culture, NPDG-F induced morphological abnormalities in merozoite cellularization during schizogony in both the Plasmodium blood and liver stages. Our data provide chemical validation that PfActin1 is an attractive, pan-lifecycle target and inform strategies for the design of more selective inhibitors.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Tiantian Jiang
Department of Pediatrics, School of Medicine, University of California
Jin Woo Lee
College of Pharmacy, Duksung Women’s University
Jennifer E. Collins
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida
Samuel Schaefer
Department of Pediatrics, School of Medicine, University of California
Daisy Chen
Flore Nardella
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida
Karen Wendt
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan
Thilini G. Peramuna
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan
Raphaella Paes
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida
James L. McLellan
Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio
Jasveen Bhasin
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida
Gregory L. Durst
Lgenia Inc.
Kirsten K. Hanson
Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio
Debopam Chakrabarti
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida
Robert H. Cichewicz
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan
Elizabeth A. Winzeler